The apolipoprotein E polymorphism is a genetic determinant of low-density lipoprotein (LDL) cholesterol. Its status as a risk factor for coronary artery disease (CAD), either through a causal relation with LDL cholesterol level or independently, is less clearly established. Data from the Multiple Risk Factor Intervention Trial were used to examine the influence of apolipoprotein E phenotype on risk of coronary events. Of the 12,866 randomized participants, 619 were studied in a nested case-control design. CAD deaths (93) and nonfatal myocardial infarctions (113) were matched to 412 controls. The allele frequencies of apolipoprotein E in the white subset (epsilon 2 = 0.06, epsilon 3 = 0.79, and epsilon 4 = 0.15) were very similar to other nonselected white American populations, and the relation of apolipoprotein E on total and LDL cholesterol was generally similar to that seen in other studies, with the epsilon 2 allele being associated with lower and the epsilon 4 allele with higher total and LDL cholesterol. Allele frequencies were not the same for patients and control subjects. The presence of epsilon 4 was associated with an increased risk of CAD that was most evident for fatal cases. There was no relation between changes in LDL cholesterol over time during the trial and apolipoprotein E phenotypes.