The effect of apolipoprotein E polymorphism on the established relationships between glucose tolerance, plasma insulin levels, and plasma lipoprotein concentrations were investigated in a sample of women defined on the basis of apolipoprotein E phenotypes. In women with the apolipoprotein E ε2 allele (n = 22), fasting plasma insulin and glucose and insulin areas under the curve measured during an oral glucose tolerance test were positively correlated with plasma triglyceride levels (0.48 ≤ r ≤ 0.70; P < 0.05). In this group, very-low-density lipoprotein cholesterol and very-low-density lipoprotein triglyceride concentrations were positively correlated with fasting insulin levels, the insulin area, and with the ratio of insulin area to glucose area. In women (n = 24) homozygous for the apolipoprotein E ε3 allele (the most common allele), essentially similar associations were found. In contrast, in women (n = 17) with the apolipoprotein E ε4 allele, no association was found between glucose tolerance, fasting and postglucose plasma insulin levels, and plasma lipid and lipoprotein levels. These results suggest that apolipoprotein E polymorphism substantially modifies the associations between glucose tolerance, plasma insulin levels, and plasma lipoprotein concentrations. Additional analysis of the data revealed that apolipoprotein E polymorphism did not alter the relationships between body fat distribution and fasting insulin and postglucose insulin levels, but no correlation was observed between fatness indexes and glucose tolerance among apolipoprotein E ε2 carriers. Therefore, the mechanisms by which apolipoprotein E polymorphism modifies plasma lipoprotein levels in a hyperinsulinemic state is not by altering the relationship of abdominal obesity to hyperinsulinemia but more likely by modifying the metabolic fate of triglyceride-rich lipoproteins in hyperinsulinemic, insulin-resistant subjects.