We investigated the effect of variation at the apolipoprotein (apo) E gene locus on the serum lipid response to a hypolipidemic diet rich in monounsaturated fatty acids (MUFA). Lipoprotein changes were assessed in 122 outpatients with type IIa (n = 70) and type IIb (n = 52) hyperlipidemia [80 men and 42 women with apo E phenotypes 3/2 (n = 27), 3/3 (n = 48), and 4/3 (n = 47)] who were switched from their basal diet containing 40% fat (22% MUFA) to an isoenergetic diet containing 31% fat (MUFA content similar to that of the basal diet) for 12 wk. Significant (P < 0.005) reductions of total, LDL, and VLDL cholesterol; triglycerides; and apo B occurred in subjects regardless of WHO phenotype. Triglycerides and VLDL cholesterol decreased more in type IIb than in type IIa subjects: 25% vs 12% and 21% vs 15%, respectively (P = 0.01). HDL cholesterol tended to decrease only in women. The heterogeneity of lipoprotein responses to dietary intervention was unrelated to apo E phenotypes. In these hyperlipidemic subjects, however, diet-induced favorable changes in serum lipoproteins were selectively influenced by WHO phenotype.