Smallpox is an infectious disease unique to humans, caused by either of two virus variants named Variola major and Variola minor.The disease is also known by the Latin names Variola or Variola vera, which is a derivative of the Latin varius, meaning spotted, or varus, meaning "pimple". The term "smallpox" was first used in Europe in the 15th century to distinguish variola from the great pox (syphilis).

Smallpox localizes in small blood vessels of the skin and in the mouth and throat. In the skin, this results in a characteristic maculopapular rash, and later, raised fluid-filled blisters. V. major produces a more serious disease and has an overall mortality rate of 30–35%. V. minor causes a milder form of disease (also known as alastrim, cottonpox, milkpox, whitepox, and Cuban itch) which kills ~1% of its victims. Long-term complications of V. major infection include characteristic scars, commonly on the face, which occurred in 65–85% of survivors. Blindness resulting from corneal ulceration and scarring, and limb deformities due to arthritis and osteomyelitis are less common complications, seen in about 2–5% of cases.

Smallpox is believed to have emerged in human populations about 10,000 BC. The disease killed an estimated 400,000 Europeans each year during the 18th century (including five reigning monarchs), and was responsible for a third of all blindness. Between 20 and 60% of all those infected—and over 80% of infected children—died from the disease.

During the 20th century, it is estimated that smallpox was responsible for 300–500 million deaths. As recently as 1967, the World Health Organization (WHO) estimated that 15 million people contracted the disease and that two million died in that year.After successful vaccination campaigns throughout the 19th and 20th centuries, the WHO certified the eradication of smallpox in 1979. To this day, smallpox is the only human infectious disease to have been completely eradicated from nature.