Although basic research suggests that vitamins may have an important role in the prevention of cardiovascular disease (CVD), the data from cohort studies and clinical trials are inconclusive. We explored the association of vitamin E, ascorbic acid (vitamin C), and multivitamins with CVD and total mortality in a large prospective cohort study of 83 639 male physicians without history of CVD or cancer residing in the United States. At baseline, use of vitamin E, vitamin C, and multivitamin supplements was provided by a self-administered questionnaire. Mortality from CVD and coronary heart disease (CHD) was assessed by death certificate review. Use of supplements was reported by 29% of the participants. During a mean follow-up of 5.5 years, there were 1037 CVD deaths including 608 CHD deaths. In this large cohort of apparently healthy US male physicians, self-selected supplementation with vitamin E, vitamin C, or multivitamins was not associated with a significant decrease in total CVD or CHD mortality. Data from ongoing large-scale randomized trials will be necessary to definitely establish small potential benefits of vitamin supplements on subsequent cardiovascular risk.