Smallpox is one of the deadliest diseases in human history and the only human infection ever wiped from the planet. Caused by the variola virus, smallpox killed roughly three in ten of the people it infected and left many survivors scarred or blind, until a worldwide vaccination campaign led the World Health Organization to declare it eradicated in 1980. No natural case has occurred since 1977. This guide explains what smallpox was, how its symptoms and rash set it apart from chickenpox, how it spread, how it was diagnosed, and how the vaccines and antiviral drugs built for it now protect against related orthopoxviruses such as mpox.
What is smallpox?
Smallpox was a serious, highly contagious disease caused by the variola virus, a member of the orthopoxvirus family that also includes cowpox, vaccinia, and the virus behind mpox. It came in two main forms: variola major, the severe and common type that killed about 30 percent of the people who caught it, and variola minor, a milder form fatal in roughly one in a hundred cases. Unlike most infections, smallpox had no animal reservoir and passed only between people, which is precisely what made global eradication possible.
Today the variola virus no longer circulates anywhere in nature. Known stocks are kept in just two high-security laboratories, one at the United States Centers for Disease Control and Prevention and one in Russia, held for research under strict international oversight. Because the virus still exists in those freezers, and because most people alive today have never been vaccinated, public health agencies now treat smallpox mainly as a potential bioterrorism threat rather than a naturally occurring illness.
Symptoms of smallpox
After exposure, smallpox stayed silent for an incubation period of about 7 to 19 days, during which the infected person felt well and was not contagious. The illness then began abruptly with high fever, severe headache, backache, and exhaustion. This early phase lasted two to four days before the rash appeared.
The rash was the hallmark of smallpox. It usually started as flat red spots in the mouth and on the face, then spread to the arms, legs, hands, and feet. Over about two weeks the spots became raised bumps, then firm, deep blisters, then pus-filled pustules that crusted and scabbed. What set the rash apart from the itchy blisters of chickenpox was its pattern: the lesions clustered on the face and limbs rather than the trunk, and they all moved through each stage at the same time, so a patient’s spots looked uniform rather than mixed. To see how different that looked from an itchy rash that arrives in waves, compare the varicella (chickenpox) symptoms, causes, treatments, and prevention guide.
| Stage or feature | What it looked or felt like |
|---|---|
| Incubation period | About 7 to 19 days with no symptoms and no spread to others |
| Prodrome (early illness) | Sudden high fever, severe headache, backache, and fatigue lasting two to four days |
| Early rash | Small red spots in the mouth and on the face that spread to the arms and legs |
| Blisters and pustules | Firm, deep lesions that filled with fluid and then pus over roughly a week |
| Scabs and scars | Pustules that crusted, scabbed, and separated, often leaving pitted scars |
| Distribution and timing | More lesions on the face and limbs than the trunk, all at the same stage at once |
How smallpox spread: causes and risk factors
The single cause of smallpox was infection with the variola virus. It passed mainly from person to person through respiratory droplets released during prolonged, face-to-face contact, which is why household members and caregivers were at greatest risk. Less often, the virus spread through contaminated bedding, clothing, or other materials that had touched a patient’s sores. A person became contagious once the fever and rash began and stayed contagious until the last scab fell off.
Because the disease has been eradicated, no one faces a natural risk of smallpox today. Historically, the people most exposed were the unvaccinated, close contacts of a sick person, and those living in crowded conditions where droplets spread easily. Health care workers and family caregivers bore much of that risk before vaccination became widespread. Like the airway-spread illness you can review in the measles symptoms, causes, treatments, and management guide, smallpox thrived wherever susceptible people gathered indoors.
Smallpox and its relative mpox
Smallpox may be gone, but its viral family is not. The variola virus belongs to a group called orthopoxviruses, and its best-known living relative is the virus that causes mpox, formerly monkeypox. The two diseases share a similar pox rash and are fought with the same tools: the JYNNEOS vaccine and the antiviral tecovirimat were both developed against smallpox and are now used for mpox. When mpox spread internationally beginning in 2022, it renewed interest in this whole family of viruses and in the stockpiles built for smallpox defense.
For most readers, that is the practical reason smallpox still matters: it helps make sense of a related infection that is still circulating. Other blistering rashes cause confusion too, so to tell them apart it helps to read the guide to shingles symptoms, causes, and treatments, which describes a different virus that also produces painful skin lesions.
How smallpox is diagnosed
Because smallpox has been eradicated, there is no routine blood test for it that an ordinary person would ever be offered. Any real diagnosis today would begin with the clinical picture, the distinctive rash in someone who could plausibly have been exposed, and would be confirmed only at a specialized high-containment laboratory. Confirmation has always rested on finding the virus itself, not on a test you could order at a clinic.
The main laboratory tools are molecular and microscopic. Clinicians would confirm a suspected case with molecular testing, so it helps to read what an RT-PCR test reveals about a virus’s genetic material taken from a lesion, while specialized labs can also see the brick-shaped poxvirus particles under an electron microscope. Blood tests play a supporting role by tracking the immune response: laboratories can review what IgM antibodies reveal on a blood test as a sign of recent infection, and clinicians can also understand what IgG antibodies reveal about past infection or immunity. A viral infection also shifts the white cells that fight it, so a clinician might see what a lymphocyte count reveals on a blood test as part of the wider picture. These same methods are how the related orthopoxvirus behind mpox is diagnosed today.
| Test | What it detects | Where it fits |
|---|---|---|
| Molecular test (PCR) | Viral genetic material from a lesion swab | The main confirmatory test, performed only in specialized labs |
| Electron microscopy | Brick-shaped poxvirus particles | Rapid identification of a poxvirus at reference laboratories |
| IgM antibody test | The body’s early immune response | Supporting evidence of recent orthopoxvirus infection or vaccination |
| IgG antibody test | Longer-lasting antibodies | A marker of past infection or vaccine-related immunity |
Treatment and supportive care
For most of history there was no specific treatment for smallpox, so care meant easing symptoms, keeping patients hydrated and comfortable, preventing bacterial infection of the open sores, and isolating the sick to stop the spread. That supportive approach did not cure the infection; the body either overcame it or did not.
Modern biodefense has changed the picture on paper. Several antiviral drugs have since been developed and stockpiled in case smallpox ever reappears. Tecovirimat, sold as TPOXX, is the leading option; it was approved on laboratory and animal data, since it could not ethically be tested in people sick with a disease that no longer exists. Brincidofovir (Tembexa) and cidofovir are additional options held for emergencies. An important honesty check comes from smallpox’s close relative mpox: recent randomized trials found that tecovirimat did not significantly shorten mpox illness for either clade of the virus, tempering expectations about how much these drugs would help in a real smallpox event. They remain part of preparedness rather than proven cures, and a suspected orthopoxvirus infection should be managed by clinicians.
Prevention
Prevention is the great success story of smallpox. A vaccine, one of the first ever developed, is what drove the virus to extinction. Routine childhood vaccination ended in the United States in 1972 and worldwide after eradication, so most people today carry no immunity. Vaccines are still made and stockpiled, and only a limited group receives them: certain laboratory workers who handle orthopoxviruses, some military personnel, and outbreak responders.
Two vaccines are central today. ACAM2000 uses a live related virus called vaccinia and can cause a sore and small scar at the injection site and, rarely, more serious side effects. The newer MVA-BN vaccine, sold as JYNNEOS, uses a weakened virus that cannot replicate in the body, which makes it safer for people with weakened immune systems. JYNNEOS is the same vaccine now used to protect against mpox, which is why smallpox-era science has become suddenly relevant again.
Complications and long-term outlook
Among survivors, smallpox often left lasting marks. The deep pustules healed into permanent pitted scars, most visibly on the face, and the disease could damage the eyes badly enough to cause blindness. Variola major killed about three in ten of those infected, with higher rates in infants and in the severe hemorrhagic and flat forms. Secondary bacterial infection of the open sores was a common and dangerous complication, sometimes reflected in the white blood cell changes a clinician would track.
The broader outlook, though, is the most hopeful in all of medicine. Because smallpox spread only between humans and a good vaccine existed, a coordinated global campaign cornered and eliminated it entirely. That success is why smallpox is discussed in the past tense, and why its lessons now guide the response to its living relatives.
Latest scientific advances in smallpox and mpox research
Because smallpox no longer occurs, the most useful recent science comes from its close relative mpox, where the same drugs and vaccines can be studied in patients. According to research indexed in PubMed, a 2025 review of tecovirimat clinical trials concluded that the two largest randomized studies, STOMP and PALM007, did not show the drug shortened mpox illness, even though earlier case reports had looked encouraging (Dobrek, 2025). What this means for you: tecovirimat is stockpiled for smallpox emergencies, but the best current evidence says it is not a proven cure, and a real case would still depend heavily on supportive care.
A broad 2025 review of mpox found that the two-dose MVA-BN vaccine, the same JYNNEOS shot developed for smallpox, had a favorable safety record and promising effectiveness at preventing mpox, including in people with weakened immune systems (Viguier et al., 2025). What this means for you: the non-replicating vaccine designed for smallpox is the most reassuring tool in this family, and for eligible people it is the practical way to reduce risk from the orthopoxvirus still circulating.
Researchers are also building the next generation of countermeasures. A 2026 laboratory study isolated human antibodies from people who had received a vaccinia-based vaccine and showed they could block orthopoxviruses, including the mpox virus, from spreading between cells and protect mice from a lethal challenge (Zhang et al., 2026). What this means for you: this is early, preclinical work rather than a treatment you could request today, but it points toward targeted antibody therapies that could one day supplement today’s vaccines and antivirals.
Glossary of key terms
| Term | Definition |
|---|---|
| Variola virus | The orthopoxvirus that caused smallpox; it no longer circulates in nature. |
| Orthopoxvirus | A family of related viruses that includes smallpox, cowpox, vaccinia, and mpox. |
| Eradication | The permanent, worldwide elimination of a disease, achieved for smallpox in 1980. |
| Variola major | The common, severe form of smallpox that killed about 30 percent of those infected. |
| Variola minor | A milder form of smallpox that was fatal in roughly one percent of cases. |
| Incubation period | The 7-to-19-day gap between exposure to the virus and the first symptoms. |
| Pustule | A raised, pus-filled skin lesion characteristic of the smallpox rash. |
| Tecovirimat (TPOXX) | An antiviral drug stockpiled for smallpox and also used against mpox. |
| MVA-BN (JYNNEOS) | A non-replicating vaccine that protects against both smallpox and mpox. |
Frequently asked questions
Is smallpox still around today?
No. Smallpox is the only human disease ever eradicated. The World Health Organization declared it gone in 1980, and no natural case has occurred since 1977. The variola virus survives only in two secure laboratories, one in the United States and one in Russia, where it is kept for research under strict controls. The main modern concern is the small chance it could be misused as a bioterrorism agent, which is why vaccines and antivirals are still stockpiled.
What were the main symptoms of smallpox?
Smallpox began, after an incubation period of about 7 to 19 days, with a sudden high fever, severe headache, backache, and fatigue. Two to four days later a distinctive rash appeared, starting on the face and spreading to the arms and legs. The spots turned into firm, deep blisters and then pus-filled pustules that scabbed over about two weeks, often leaving permanent scars. Unlike chickenpox, all the lesions progressed through each stage at the same time.
How was smallpox eradicated?
Smallpox was eliminated through a coordinated global vaccination campaign led by the World Health Organization during the 1960s and 1970s. Two features made success possible: the virus infected only humans, with no animal reservoir to hide in, and an effective vaccine already existed. Health teams used a strategy of finding each outbreak and vaccinating everyone around it, called ring vaccination, until the chain of transmission was broken everywhere. The last natural case was recorded in 1977.
Is there a treatment or cure for smallpox?
No treatment has ever been proven to cure people sick with smallpox, partly because the disease disappeared before modern antivirals existed. Care was supportive: fluids, comfort, wound care, and isolation. Today, antivirals including tecovirimat (TPOXX), brincidofovir, and cidofovir are stockpiled for emergencies, but they were approved on laboratory and animal data. Trials of tecovirimat against the related mpox virus did not show it shortened illness, so it is best seen as preparedness rather than a guaranteed cure.
Can you still get the smallpox vaccine, and who needs it?
Routine smallpox vaccination ended decades ago because the disease was gone, so most people are neither vaccinated nor at risk. Vaccines are still produced and stockpiled, and a limited group receives them: some laboratory workers who handle orthopoxviruses, certain military personnel, and people involved in outbreak response. The older ACAM2000 vaccine can leave a small scar, while the newer JYNNEOS (MVA-BN) vaccine is safer for people with weakened immune systems and is also used against mpox.
How is smallpox different from chickenpox and mpox?
Despite the shared word pox, chickenpox is caused by a completely unrelated virus and produces itchy blisters that appear in waves, so a person has spots at several different stages at once. Smallpox lesions were deeper, more concentrated on the face and limbs, and all at the same stage together. Mpox, by contrast, is a true relative of smallpox in the orthopoxvirus family; it causes a milder, similar-looking illness and is prevented and treated with the same vaccine and antiviral developed for smallpox.
Sources
- Centers for Disease Control and Prevention — About Smallpox — CDC Smallpox, 2024 — cdc.gov
- Centers for Disease Control and Prevention — Treatment of Smallpox — CDC Smallpox, 2024 — cdc.gov
- Cleveland Clinic — Smallpox: Symptoms, Causes and Treatment — Cleveland Clinic Health Library, 2023 — my.clevelandclinic.org
- MedlinePlus, National Library of Medicine — Smallpox — MedlinePlus Health Topics — medlineplus.gov
- World Health Organization — Smallpox — WHO Health Topics — who.int
- Dobrek Ł — Tecovirimat for the treatment of monkeypox: a review of clinical trials — Przeglad Epidemiologiczny, 2025 — doi.org/10.32394/pe/214793
- Viguier C, Delobel P, Lescure FX, et al. — From neglected to notoriety: a review of mpox clinical features, virology, epidemiology, treatment and prevention strategies — European Journal of Clinical Microbiology & Infectious Diseases, 2025 — doi.org/10.1007/s10096-025-05242-1
- Zhang J, Hao Y, Li D, et al. — Human monoclonal antibodies from donors vaccinated with recombinant vaccinia vaccine targeting A35 and B6 effectively inhibit orthopoxvirus spread and infection — Antiviral Research, 2026 — doi.org/10.1016/j.antiviral.2026.106466
Further reading
- Read about another disease driven to the brink of extinction by vaccination by reviewing the polio guide to symptoms, causes, treatments, and management.
- Explore a vaccine-preventable childhood infection by reading the mumps symptoms, causes, treatments, and prevention guide.
- Compare another illness known for a body-wide rash by reading the scarlet fever symptoms, causes, and treatment guide.
- Learn how a routine blood count reflects infection by reviewing what neutrophil levels reveal on a blood test.
- Build a fuller picture of your own results with this guide to reading reference ranges, flags, and trends in a lab report.
Understand your lab results with BloodSense
Smallpox itself was eradicated decades ago, so there is no routine test for it that you would ever encounter. What remains relevant is how its close relatives, such as mpox, are evaluated today: through laboratory testing and the blood work that tracks your immune response to any viral infection. Those reports can be hard to read on your own, full of antibody names, reference ranges, and flagged values that are easy to misread.
BloodSense translates a full lab report into plain language, showing where each marker sits relative to its reference range and helping you understand what a high, low, or borderline result may mean for your health. Get your results interpreted in minutes
