Objective: To examine the association between the apolipoprotein E (APOE) gene and early age-related maculopathy (ARM) in middle-aged persons. Design: Population-based cross-sectional study. Participants: Participants from the Atherosclerosis Risk in Communities Study (n = 10 139; age range, 49-73 years). Methods: Retinal photography was performed on 1 randomly selected eye, and grading for presence of ARM was carried out using a modification of the Wisconsin ARM Grading System. Early ARM was defined as the presence of either soft drusen alone, retinal pigment epithelial depigmentation alone, or a combination of soft drusen with increased retinal pigment and/or depigmentation. DNA extracted from blood samples of participants were analyzed for common allelic variants of the APOE gene (ε2, ε3, and ε4). Main Outcome Measures: Presence of early ARM on retinal photographs. Results: The prevalence of early ARM was similar in participants with different APOE genotypes: ε2/ε2 (5.9%), ε2/ε3 (5.2%), ε2/ε4 (3.2%), ε3/ε3 (5.2%), ε3/ε4 (4.9%), and ε4/ε4 (4.1%). After controlling for age, gender, race, cigarette smoking, and other factors, early ARM was not associated with APOE genotypes, with an odds ratio (OR) of 1.35 (95% confidence interval [CI], 0.54-3.38) for ε2/ε2 genotype, an OR of 1.06 (95% CI, 0.80-1.40) for ε2/ε3 genotype, an OR of 0.63 (95% CI, 0.32-1.24) for ε2/ε4 genotype, an OR of 0.99 (95% CI, 0.80-1.24) for ε3/ε4 genotype, and an OR of 0.88 (95% CI, 0.47-1.63) for ε4/ε4 genotype, as compared with ε3/ε3 genotype (reference). No associations were found for specific early ARM signs or in analyses stratified by age, gender, race, or cigarette smoking status. Conclusions: These data provide no evidence of a strong association between the APOE gene and early ARM in middle-aged persons. This suggests that APOE is not likely a major determinant of the early stages of ARM in younger people. However, our study does not exclude the possibility of a weaker association or that APOE may influence only the development of late ARM in older populations, as reported in other studies.