The relation of serum total homocysteine and lipoprotein(a) (Lp(a)) with the incidence of atherosclerotic disease was investigated among 7424 men and women aged 40-64 years free of atherosclerotic disease at baseline in 1977. During the 9-year follow-up, 134 male and 131 female cases with either myocardial infarction or stroke were identified. For each case a control subject was selected belonging to the same sex and 5-year age group. Serum samples collected in 1977 were stored at -20 degrees C and analyzed in 1991. The mean serum homocysteine concentration of male cases and controls was 9.99 mumol/l and 9.82 mumol/l at baseline and that of female cases and controls 9.58 mumol/l and 9.24 mumol/l, respectively. The median serum Lp(a) concentration of male cases and controls was 73 mg/l and 108 mg/l and that of female cases and controls 113 mg/l and 91 mg/l, respectively. The differences between cases and controls were not statistically significant. There was also no significant association between either homocysteine or Lp(a) and atherosclerotic disease, myocardial infarction or stroke in logistic regression analyses. The odds ratios varied from 1.00 to 1.26 for homocysteine and from 0.81 to 1.06 for Lp(a). The results of this prospective population-based study do not support the hypotheses that serum homocysteine or Lp(a) are risk factors for atherosclerotic disease. The lack of association between serum homocysteine and atherosclerotic disease may be due to the exceptionally low gene frequency predisposing to homocysteinemia in Finland.