A geographically based observational study of 852 nondiabetic Hispanic and non-Hispanic white persons in southern Colorado aged 20-74 y was conducted to determine whether diet-lipid associations were modified by the apolipoprotein E (apoE, protein; APOE, gene) polymorphism. Subjects were seen for up to three visits from 1984 to 1992. A 24-h diet recall was collected and fasting serum lipid concentrations were measured at all visits. In longitudinal-regression analyses, dietary factors were significantly associated with serum lipid concentrations in the directions expected based on the large amount of literature on this topic. The positive relation between dietary cholesterol and serum total and low-density-lipoprotein cholesterol was strongest in Hispanic subjects with the APOE*2 allele (E2/ 2,3/2 genotypes) and non-Hispanic white subjects with the APOE*3 allele (E3/3 genotype), and there was no association in subjects with the APOE*4 allele (E4/3, 4/4 genotypes) in either ethnic group. No other statistically significant differences in the relations between dietary factors and serum lipid concentrations by APOE polymorphism were identified. These findings suggest that the APOE polymorphism plays only a minor role in modifying the association between dietary factors and serum lipids.