Association between apolipoprotein E (apoE) gene polymorphism and lipid levels was studied in 164 nondiabetic first-degree relatives of persons with diabetes and 962 nondiabetic persons with no family history of diabetes. Sex-specific genotypic distribution of apoE polymorphism did not differ between persons with and without a family history of diabetes. In first-degree relatives, lipid levels did not differ among persons with apoE2 (E2/2, E2/3), apoE3/3, and apoE4 (E4/4, E3/4) after adjusting for age, waist circumference, smoking, and alcohol and estrogen use. In persons without a family history of diabetes, both men (p<0.01) and women (p<0.001) with apoE2 showed lower levels of total and low density lipoprotein cholesterol compared with persons with apoE3/3 and apoE4. In women with a family history of diabetes, persons with apoE4 had larger waist circumference (p<0.05). ApoE2 allele is associated with more favorable levels of total and low density lipoprotein cholesterol in men and women without a family history of diabetes. ApoE4 allele is associated with obesity independent of dyslipidemia in women but not men with a family history of diabetes. ApoE polymorphism is not associated with lipids in men or women with a family history of diabetes.