Our objective was to establish the role of the apoprotein (apo) E phenotype in determining serum cholesterol levels in infants fed exclusively on high-fat, high-cholesterol human milk and in those fed a low-cholesterol, high-unsaturated fat formula. The total and lipoprotein cholesterol, apoB, and triglyceride concentrations in serum were quantified and related to the apoE phenotype in 151 infants at birth and at 2, 6, 9, and 12 months of age. Forty-four had the E3/4 or 4/4 phenotype (E4 group), 94 had the E3/3 phenotype (E3 group), and 13 had the E2/3 or 2/4 phenotype (E2 group). In cord blood, cholesterol concentrations tended to be higher in the E4 than in the E2 group. With exclusive breast-feeding, the concentrations rose significantly faster and higher in the E4 group than in the E3 group or, especially, the E2 group. The values (mmol/L, mean +/- SEM) were 1.6 +/- 0.15, 1.5 +/- 0.05, 1.4 +/- 0.1 (P = n.s.) at birth; 4.2 +/- 0.1, 3.8 +/- 0.08, 3.4 +/- 0.2 (P < 0.001) at 2 months; 4.4 +/- 0.15, 3.9 +/- 0.1, 3.4 +/- 0.15 (P < 0.001) at 4 months; 4.3 +/- 0.17, 4.0 +/- 0.13, 3.7 +/- 0.26 (P < 0.001) at 6 months; 4.8 +/- 0.28, 4.4 +/- 0.11, 3.8 +/- 0.05 (P < 0.001) at 9 months; and 4.7 +/- 0.11, 4.4 +/- 0.08, 4.1 +/- 0.19 (P < 0.001) at 12 months, for the E4, E3, and E2 groups, respectively. Increases in LDL cholesterol and LDL apoB behaved similarly. The total triglyceride, and total HDL, HDL2, and HDL3 cholesterol concentrations did not depend on the apoE phenotype. Among infants fed high-fat, high-cholesterol human milk, the total and LDL-cholesterol concentrations and the LDL apoB concentration of those with the apoE phenotype 4/4 or 3/4 rose faster and to higher levels than in other infants. Among formula-fed infants, receiving a low-cholesterol, high-unsaturated fat diet, the differences between the apoE groups were smaller.