Background and Purpose Apolipoprotein E (apoE) polymorphism affects plasma cholesterol and may influence risk of atherosclerosis. We investigated the association of apoE with carotid artery wall thickening (an index of atherosclerosis) in individuals with and without coronary artery disease (CAD). Methods ApoE phenotypes were resolved in 260 individuals equally represented by angiographically determined CAD case subjects and disease-free control subjects. Carotid artery intima-media thickening (IMT) was evaluated by B-mode ultrasound. Associations of apoE (E2, E3, or E4) with risk factors and IMT were evaluated in general linear models adjusted for age, sex, and CAD status with and without other traditional risk factors. Results Total cholesterol (TC) and LDL cholesterol were associated with apoE isoforms. Mean TC and LDL cholesterol were lower in E2 (n=33) carriers than E3 (n=155) and E4 (n=66) carriers (each P <.001). IMT also varied by apoE. E2 carriers had less common carotid IMT than E3 and E4 carriers ( P <.01), while internal carotid IMT was less in E2 and E3 carriers than in E4 carriers ( P <.02). Bifurcation IMT was not associated with apoE ( P =.24). ApoE polymorphism remained associated with common ( P <.01) and internal ( P <.04) IMT, and the association of apoE with mean IMT of all sites reached significance ( P <.04) after adjustment for age, sex, CAD status, TC, LDL cholesterol, HDL cholesterol, triglycerides, diabetes, hypertension, and smoking. Conclusions ApoE polymorphism is associated with segment-specific carotid IMT. The association of apoE with carotid IMT was statistically independent of apoE-associated variation in LDL cholesterol levels.