CONTEXT: The United States recently implemented smallpox vaccination of selected military personnel in a national program of preparedness against use of smallpox as a biological weapon. The resumption of smallpox vaccinations raises important questions regarding implementation and safety. OBJECTIVE: To describe the US military smallpox vaccination program. DESIGN: Descriptive study of the vaccination program from its inception on December 13, 2002, through May 28, 2003. SETTING: US Department of Defense (DoD) fixed and field medical treatment facilities on multiple continents and ships at sea. SUBJECTS: US service members and DoD civilian workers eligible for smallpox vaccination. MAIN OUTCOME MEASURES: Numbers of vaccinations and rates of vaccination exemptions, symptoms, and adverse events. Data were collected via reports to headquarters and rigorous surveillance for sentinel events. RESULTS: In 5.5 months, the DoD administered 450 293 smallpox vaccinations (70.5% primary vaccinees and 29.5% revaccinees). In 2 settings, 0.5% and 3.0% of vaccine recipients needed short-term sick leave. Most adverse events occurred at rates below historical rates. One case of encephalitis and 37 cases of acute myopericarditis developed after vaccination; all cases recovered. Among 19 461 worker-months of clinical contact, there were no cases of transmission of vaccinia from worker to patient, no cases of eczema vaccinatum or progressive vaccinia, and no attributed deaths. CONCLUSIONS: Mass smallpox vaccinations can be conducted safely with very low rates of serious adverse events. Program implementation emphasized human factors: careful staff training, contraindication screening, recipient education, and attention to bandaging. Our experience suggests that broad smallpox vaccination programs may be implemented with fewer serious adverse events than previously believed.