If used as a biological weapon, smallpox could be a serious threat to the civilian population because of its case fatality rate of 30 percent among unvaccinated people. The World Health Organization eradicated smallpox in 1977. Routine vaccination in the United States stopped in 1972, leaving about 114 million people (or 42 percent of the population) in 1998 who had not been vaccinated. In a highly susceptible, mobile population, smallpox would be able to spread widely and rapidly throughout this country and the world. Smallpox spreads primarily by droplets or aerosols from the nose and mouth of infected people or by direct contact. Contaminated clothing or bedding can spread the virus. At the end of a 12- to 14-day incubation period, a patient typically experiences high fever, malaise, headaches and backaches. Within one or two days a rash develops, mostly on the face, becoming pustular. The discovery of a single suspected case of smallpox must be treated as an international health emergency and be brought to the attention of national health officials. Laboratory confirmation is important. Currently, the best therapy that can be offered to a patient is antibiotics for treatment of secondary bacterial infection. No antiviral substances have been proven effective for the treatment of smallpox. Individuals suspected of having smallpox should be isolated immediately and all household and other face-to-face contacts should be vaccinated and placed under surveillance. In hospitals, patients should be confined to rooms that are equipped with high-efficiency particulate air filtration. Standard precautions using gowns, gloves, and masks should be observed. Laundry should be put in biohazard bags. Research should be directed to three areas: vaccines, immunotherapy and drugs, and diagnostics. At least 40 million doses of vaccine should be available in case of an epidemic. Tables, references