Technical Abstract: PURPOSE: Polymorphism of the apolipoprotein E (APOE) gene has been associated with dyslipidemia and cardiovascular disease. This study examines the association of APOE polymorphisms and diabetic retinopathy. DESIGN: Population-based cross-sectional study. METHODS: We studied 1,398 people aged 49 to 73 years with diabetes selected from four United States communities. We performed retinal photography on one randomly selected eye and graded for the presence and severity of diabetic retinopathy using a modification of the Early Treatment Diabetic Retinopathy Study scale. We performed genotyping of common polymorphic APOE alleles using polymerase chain reaction on genomic DNA from venous blood leukocytes. RESULTS: The prevalence of diabetic retinopathy and hard exudates was 15.0% and 5.3% in Caucasians (n = 935), and 24.6% and 9.7% in African-Americans (n = 463), with type 2 diabetes. APOE gene polymorphisms were not associated with diabetic retinopathy in either Caucasians or African-Americans. In African-Americans, the epsilon 2/epsilon 4 genotype (n = 6) was associated with increased prevalence of hard exudates (odds ratio [OR] 4.10, 95% confidence interval [CI] 1.30 to 12.90), as was the epsilon 2/epsilon 3 genotype (n = 9, OR 2.64, 95% CI 1.01 to 6.95). No association between APOE genotypes and hard exudates was found in Caucasians. CONCLUSIONS: These data suggest that APOE gene polymorphisms are not associated with diabetic retinopathy in either Caucasians or African-Americans with type 2 diabetes.