Polymorphisms in the apolipoprotein E (apoE) phenotype (especially E4) are associated with increased cardiovascular risk and particularly with increased concentrations of LDL cholesterol. Little is known, however, about whether alterations in LDL size are associated with the apoE4 phenotype. LDL size was determined by gradient gel electrophoresis, and apoE phenotype was determined by isoelectric focus in 337 nondiabetic subjects from the San Antonio Heart Study, a population-based study of diabetes and cardiovascular risk factors in Mexican Americans and non-Hispanic whites. ApoE4 was associated not only with increases in LDL cholesterol concentrations but also with decreased LDL size. After adjustment for age, sex, body mass index, waist-to-hip ratio, triglyceride, HDL cholesterol, fasting insulin, and diabetic status, the apoE phenotype remained significantly related to LDL size (A) in both men (apoE23, 260.0; apoE33; 256.3; and apoE34, 252.6; P = .01) and women (apoE23, 261.7; apoE33, 257.9; and apoE34, 256.7, P = .045). Variations in apoE phenotype are associated not only with changes in the absolute concentration of LDL cholesterol but also with changes in its composition. These changes are only partly explained by associations of apoE with insulin, triglyceride, and HDL cholesterol.