High circulating total homocysteine (tHcy) concentration, which is influenced by folate and vitamin B-12 status, is a suspected cause of cardiovascular events. This relation has been investigated in both case-control and prospective studies but has not been evaluated for different sex x age subgroups of the general U.S. population. We used data on adult (i.e., aged > or =40 y) male (n = 1097) and female (n = 1107) participants in the third National Health and Nutrition Examination Survey, excluding diabetics and those supplemented with estrogen, vitamins or minerals, to evaluate the association between serum tHcy concentration and self-report of heart attack or stroke. After adjustment for age, race-ethnicity, smoking, blood pressure, blood pressure medication, body mass index and serum concentrations of creatinine and cholesterol, past events were reported 2.4 (95% confidence interval 1.0-5.5) times as often by men with tHcy concentration of >12 micromol/L as by men with lower values. The odds ratio for women was 2.6 (95% confidence interval 1.1-6.6) after adjustment for the same factors plus menopausal status. A stronger relation in men aged < or =60 y compared with older men may help reconcile conflicting results of earlier studies.