The association between apolipoprotein (apo) genetic polymorphisms and lipid phenotypes remains to be determined because such studies have reported contradictory results. We have measured plasma total cholesterol (TC) and HDL cholesterol (HDL-C) in a cross-sectional sample of 1328 (462 men and 866 women) Japanese (aged 40 to 80 years) and analyzed their DNA for the following genotypes: apoA1-C3 Msp I and Sst I sites; apoB signal peptide insertion/deletion, Xba I site and 3' variable number of tandem repeats (VNTR); and apoE. Using multivariate analyses (ANOVA) we found that (1) the polymorphisms of apoA1-C3 and apoB genes are not significantly associated with TC or HDL-C and (2) the polymorphism of the apoE gene is significantly related with TC and the TC:HDL-C ratio. The epsilon 2 carriers have lower levels of TC and a lower TC:HDL-C ratio, epsilon 3 carriers have intermediate levels, and epsilon 4 carriers have higher levels. These findings held whether sexes were analyzed separately or together. Although an opposite trend in HDL-C levels was observed, it did not reach the level of statistical significance. Multiple regression analyses have shown that apoE polymorphism accounts for about 2.3% of the variation in TC and TC:HDL-C ratio irrespective of sex. When the subjects are divided into two groups according to their age (< or = 59 and > or = 60 years old), the effect of apoE alleles on serum cholesterols appears to be diluted in the younger age group whereas it appears to be accentuated in the older group for both sexes. Our findings suggest that among the apo genetic polymorphisms examined, the apoE gene may be considered as a possible candidate for the "high-risk" strategy of atherosclerosis prevention in the Japanese population.