Recent anthrax attacks in the United States have raised concern about the nation's vulnerability to a smallpox attack. Many strategies have been suggested to minimize the impact of such an attack, ranging from quarantine and vaccination of case contacts to resumption of routine vaccination. Before the latter strategy is adopted, an understanding of the likely consequences of mass vaccination is essential.Number of adverse events resulting from two vaccination campaigns: vaccinating persons 1 to 29 years of age and vaccinating those 1 to 65 years of age.Number of adverse events = incidence rate of adverse events x number vaccinated. We assumed 75% vaccine uptake in the target group (i.e., we estimated that about 25% of potential vaccine recipients would be excluded because they are, or have close contact with, individuals who have eczema or are immunocompromised).Historical data on the incidence of adverse events from smallpox vaccination were identified by a literature search. Number vaccinated was drawn from the January 2000 U.S. Census estimate.Fever (<1 case per 5 vaccine recipients) and rash (<1 case per 100 vaccine recipients) would be the most common adverse events. Serious adverse events, including encephalitis (<3 cases per million) and death (<2 cases per million), although rare, would be more common than with other currently recommended vaccines. After excluding high-risk individuals and their contacts, we estimate that a vaccination strategy directed at people aged 1 to 29 years would result in approximately 1600 serious adverse events and 190 deaths. Vaccinating people aged 1 to 65 years would result in approximately 4600 serious adverse events and 285 deaths.While advances in health care over the past three decades could mitigate vaccine complications, the increased number of unimmunized high-risk individuals (e.g., those with eczema or immune suppression) could increase complication rates.The decision to resume smallpox vaccination depends on weighing the likelihood of a smallpox attack and its anticipated mortality against expected harm from a mass immunization program. Smallpox vaccine has a higher complication rate than any other vaccine currently being used. Careful prevaccination exclusion of high-risk individuals and their close contacts would be essential to minimize complications of a mass vaccination campaign, although such exclusions necessarily mean that some proportion of the population will remain susceptible to smallpox.