The epsilon4 allele of apolipoprotein (APOE) is known to be associated with a number of adverse health outcomes, yet the association of the allele with depression has not been conclusively determined. The authors explored the hypothesis that the epsilon4 allele is a risk factor for depression among older persons with a low cholesterol level (a known risk factor for depression).A biracial community sample of 2,550 older African Americans and Whites in North Carolina was genotyped for APOE, tested for cholesterol, and evaluated for depression at both baseline and 4-year follow-up.No relationship was found between the epsilon4 allele and depression or low cholesterol and depression in either cross-sectional or longitudinal analyses. The interaction of the epsilon4 allele and cholesterol was also not associated with depression in controlled analyses. Female gender, less education, being unmarried, and cognitive impairment were associated with depression in cross-sectional controlled analyses; only cognitive impairment was associated with depression in longitudinal analyses.Despite the association of the epsilon4 allele with a number of adverse health outcomes, as well as the association between depression and cholesterol in previous studies, no association was found between epsilon4 and low cholesterol or depression in cross-sectional and longitudinal analyses. The interaction of epsilon4 and cholesterol was not associated with depression.