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The influence of apolipoprotein E (APOE) genotypes on plasma lipid levels was determined in 278 Mexican individuals. The most frequent genotype was E3/3 (80.5%) followed by E3/4 (12.5%), E2/3 (5.0%), E2/4 (1.4%), and E4/4 (0.3%). Our data are similar to those previously described for Mexican-American and American Indian populations, which show the highest frequency worldwide of the APOE*3 and the E3/3 genotype. Compared to female carriers of the E3/3 genotype, women with the E3/4 genotype presented increased low-density lipoprotein cholesterol (117 ± 28.0 mg/dL vs. 134.0 ± 31.7 mg/dL, p < 0.05), and total cholesterol (179.4 ± 33.4 mg/dL vs. 197.5 ± 35.4 mg/dL, p < 0.01). Also, we detected increased high-density lipoprotein concentrations in women with the E2/3 genotype (53.7 ± 19.5 mg/dL) when compared to women with the E3/3 genotype (45.2 ± 12.0 mg/dL) ( p < 0.032). Our data suggest that genetic variation at the APOE locus in the Mexican population is a genetic factor that influences plasma lipid levels. This effect was observed only in the female population. Additional studies attempting to correlate APOE polymorphism with plasma lipid profile in a large number of individuals would be helpful in establishing the true significance of this polymorphism in the Mexican population.