Apolipoprotein E allele 4 (apo ε4) and smoking each have been associated with an unfavorable lipid profile. We used data collected on 1,472 subjects in the National Heart, Lung, and Blood Institute Family Heart Study to assess whether smoking interacts with apo ε4 to influence the levels of plasma lipids. We dichotomized smoking and apo ε4 and used analysis of covariance to estimate the means of lipids. Smokers had lower body mass index, were younger, and consumed less fruits and vegetables. Among individuals without apo ε4, comparing nonsmokers with smokers, mean low density lipoprotein cholesterol (LDL) was 129.3 and 134.4 mg/dL, respectively, for women and 126.1 and 127.6 mg/dL, respectively, for men. Among subjects with an apo ε4 allele, corresponding means were 132.0, and 152.9 mg/dL, respectively, for women and 131.3 and 137.3 mg/dL, respectively, for men (P for interaction <0.001 for women and 0.11 for men). A similar interaction was observed for total cholesterol among women (P = 0.02). This study shows a statistically significant effect modification of the relation of apo ε4 to LDL and total cholesterol by smoking among women. Smoking may enhance genetic susceptibility to an unfavorable lipid profile among subjects with apo ε4.