Genetic polymorphism of apolipoprotein (apo) E is controlled by three common (epsilon 2, epsilon 2, epsilon 4) and several rare alleles (e.g., epsilon 1, epsilon 4*, epsilon 4v) at the apo E structural gene locus and may be demonstrated by isoelectric focusing of delipidated sera followed by immunoblotting. Apo E allele frequencies vary significantly between different ethnic groups. The common apo E isoforms E2 (arg158----cys) and E4 (cys112----arg) differ functionally from the parent E3 isoform, explaining their effects on the normal variance of plasma lipoprotein concentrations and their association with hyperlipidemic conditions. In all studied populations the receptor-binding defective apo E2 (arg158----cys) is associated with low cholesterol and apo B in heterozygotes and results in primary dysbetalipoproteinemia or type III hyperlipoproteinemia in homozygotes. Conversely, the epsilon 4 allele is associated with high cholesterol in Finns and Germans but less or not significantly so in Japanese or Singapore populations. In addition to their effects on the normal variance of lipoprotein concentrations, the alleles epsilon 2 and epsilon 4 are associated with hypertriglyceridemia and hypercholesterolemia, respectively. A working hypothesis explaining these observations is presented.