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Child with smallpox rash, showing the characteristic raised blisters with a central depression

Smallpox is an eradicated infectious disease of humans caused by the Variola major and V. minor viruses. V. major causes a serious disease with a mortality rate of around 30%; V. minor is associated with much milder symptoms and mortality below 1%. The virus is mainly transmitted by the respiratory route but can also be carried on contaminated objects. Smallpox preferentially infects skin cells, resulting in a usually maculopapular rash, and later, raised fluid-filled blisters. Most V. major survivors have permanent scarring, commonly on the face, which can be extensive. Less common long-term complications include blindness resulting from corneal ulceration and scarring, and in young children, limb deformities due to arthritis and osteomyelitis.

Smallpox probably emerged in human populations in about 10,000 BC; the mummified body of Egyptian pharaoh Ramses V shows evidence of smallpox rash. The disease was responsible for an estimated 300–500 million deaths during the 20th century. Smallpox vaccine, the earliest vaccine, was developed in the 18th century. After intensive vaccination campaigns, the last natural infection occurred in 1977. Smallpox was certified the first infectious disease to be eradicated globally in 1979. Debate is ongoing over whether all stocks of the virus should be destroyed.