Lipoprotein(a) [Lp(a)] is formed by the assembly of LDL particles and a carbohydrate-rich protein, apolipoprotein(a) [apo(a)], which has a high degree of structural homology with plasminogen. While the majority of retrospective studies have found an association between Lp(a) level and cardiovascular disease (CVD), the few prospective studies to date have reported contradictory results. We conducted a nested case-control study using the participants in the Stanford Five-City Project, a long-term CVD prevention trial. Participants with an incident possible or definite myocardial infarction or coronary death were matched to a single control subject for age, sex, ethnicity, residence in a treatment or control city, and time of survey. This process yielded 134 case-control pairs, 90 male and 44 female, for whom plasma was available for analysis of Lp(a). Lp(a) values in nanomoles per liter were determined by an enzyme-linked immunoassay that measures Lp(a) independently of apo(a) size polymorphism. Apo(a) size isoforms were determined by SDS-agarose gel electrophoresis. Median Lp(a) level in male cases was almost double that in control subjects (41.8 versus 21.2 nmol/L; P < .01); in female cases, median Lp(a) was 34% higher than in control subjects (32.5 versus 21.2 nmol/L), but this difference was not statistically significant. Among the male cases, there was an increased frequency of small apo(a) isoforms, while no significant difference was found in apo(a) size between female cases and control subjects. The association between Lp(a) level and case-control status in men was independent of total, HDL, and non-HDL cholesterol levels, as well as apo(a) size isoform, cigarette smoking, blood pressure, and obesity. In men, the most efficient threshold value of Lp(a) concentration for separating cases and control subjects was 35 nmol/L; the odds ratio for being a case above this level compared with below was 2.84 (95% confidence interval: 1.53-5.27, P < .001). This study provides strong evidence that Lp(a) level is a prospective, independent risk factor for developing coronary artery disease in men and indicates that the size of apo(a) may also play a role. The lack of a significant association in women deserves further evaluation in larger studies.