The apolipoprotein (apo) E phenotype and its influence on plasma lipid and apolipoprotein levels were determined in men and women from a working population of Madrid, Spain. The relative frequencies of alleles i:2, d and i:4 for the study population (n = 614) were 0.080, 0.842 and 0.078, respectively. In men, apo E polymorphism was associated with variations in plasma triglyceride and very low-density lipoprotein (VLDL) lipid levels. lt was associated with the proportion of apo C-II in VLDL, and explained 5.5% of the variability in the latter parameter. In women apo E polymorphism was associated with the concentrations of plasma cholesterol and low-density Iipoprotein (LDL) and high-density lipoprotein (HDL) related variables. The allelic effects were examined taking allele c3 homozygosity as reference. In men, allele i:2 significantly increased VLDL triglyceride and VLDL cholesterol concentrations, and this was accompanied by an increase of the apo C-II content in these particles. Allele i:4 did not show any significant influence on men's lipoproteins. In women, allele i:2 lowered LDL cholesterol and apo B levels, while allele i:4 increased LDL cholesterol and decreased the concentrations of HDL cholesterol, HDL phospholipid and apo A-1. These effects were essentially maintained after excluding postmenopausal women and oral contraceptive users from the analysis. In conclusion: (1) the population of Madrid, similar to other Mediterranean populations, exhibits an underexpression of apo E4 compared to the average prevalence in Caucasians, (2) gender interacts with the effects of apo E polymorphism: in women, it influenced LDL and HDL levels, whereas in men it preferentially affected VLDL, and (3) allele i:2 decreased LDL levels in women, while it increased both VLDL lipid levels and apo C-II content in men, but, in contrast to allele i:4, it did not show an impact on HDL in either sex.