Retrospective and cross-sectional data suggest that vigorous exertion can trigger cardiac arrest or sudden death and that habitual exercise may diminish this risk. However, the role of physical activity in precipitating or preventing sudden death has not been assessed prospectively in a large number of subjects. We used a prospective, nested case-crossover design within the Physicians' Health Study to compare the risk of sudden death during and up to 30 minutes after an episode of vigorous exertion with that during periods of lighter exertion or none. We then evaluated whether habitual vigorous exercise modified the risk of sudden death that was associated with vigorous exertion. In addition, the relation of vigorous exercise to the overall risk of sudden death and nonsudden death from coronary heart disease was assessed. During 12 years of follow-up, 122 sudden deaths were confirmed among the 21,481 male physicians who were initially free of self-reported cardiovascular disease and who provided information on their habitual level of exercise at base line. The relative risk of-sudden death during and up to 30 minutes after vigorous exertion was 16.9 (95 percent confidence interval, 10.5 to 27.0; P<0.001). However, the absolute risk of sudden death during any particular episode of vigorous exertion was extremely low (1 sudden death per 1.51 million episodes of exertion). Habitual vigorous exercise attenuated the relative risk of sudden death that was associated with an episode of vigorous exertion (P value for trend=0.006). The base-line level of exercise was not associated with the overall risk of subsequent sudden death. These prospective data from a study of U.S. male physicians suggest that habitual vigorous exercise diminishes the risk of sudden death during vigorous exertion.