Apolipoprotein E (apoE), an important determinant of plasma lipoprotein metabolism, has three common alleles (epsilon2, epsilon3, and epsilon4). Population studies have shown that the risk of diseases characterized by oxidative damage, such as coronary heart disease and Alzheimer's disease, is significantly higher in epsilon4 carriers. We evaluated the association between apoE genotypes and plasma F2-isoprostane levels, an index of lipid peroxidation, in humans. Two hundred seventy-four healthy subjects (104 males, 170 females; 46.9 +/- 13.0 yr; 200 whites, 74 blacks; 81 nonsmokers, 64 passive smokers, and 129 active smokers) recruited for a randomized clinical antioxidant intervention trial were included in this analysis. ApoE genotype was determined by PCR and restriction enzyme digestion. Free plasma F2-isoprostane was measured by GC-MS. Genotype groups were compared using multiple regression analysis with adjustment for sex, age, race, smoking status, body mass index, plasma ascorbic acid, and beta-carotene. Subjects with epsilon3/epsilon4 and epsilon4/epsilon4 genotype (epsilon4-carriers) and with epsilon2/epsilon3 and epsilon3/epsilon3 (non-epsilon4-carriers) were pooled for analysis. In subjects with high cholesterol levels (total cholesterol above 200 mg/dl), plasma F2-isoprostane levels were 29% higher in epsilon4 carriers than in non-epsilon4-carriers (P= 0.0056). High-cholesterol subjects that are epsilon4 carriers have significantly higher levels of lipid peroxidation as assessed by circulating F2-isoprostane levels.