High levels of dehydroepiandrosterone sulfate (DHEAS) have been associated with decreased risks of cardiovascular disease. The authors analyzed DHEAS in plasma collected at baseline among 169 participants in the Physicians' Health Study who subsequently had a myocardial infarction and 169 matched controls. The mean prediagnostic plasma DHEAS levels between cases (p = 0.33) (mean, 3.54 mumol/liter; standard deviation, 2.30) and controls (mean, 3.61 mumol/liter; standard deviation, 2.16) did not differ significantly. The relative risk was 1.04 (95 percent confidence interval 0.42-2.60) comparing extreme quintiles after adjustment for several coronary risk factors. In conclusion, these findings do not support the hypothesis that elevated plasma DHEAS is associated with a decreased risk of coronary disease in men, but a small to moderate association cannot be excluded.