Two hypercholesterolemic mouse models, the apo-E–deficient mouse (Apoe^−/−) and the LDL receptor–deficient mouse (Ldlr^−/−), have been used extensively as animal models of atherogenesis. Total plasma cholesterol levels in chow-fed Apoe^−/− mice are much higher than in Ldlr^−/− mice. In a recent study, we managed to even-up the cholesterol levels in Apoe^−/− mice and Ldlr^−/− mice by making both models homozygous for the Apob¹⁰⁰ (apo B-100–only) allele. On a chow diet, apo-E–deficient apo B-100–only mice (Apoe^−/−Apob^100/100) and LDL receptor–deficient apo B-100–only mice (Ldlr^−/−Apob^100/100) had similar total plasma cholesterol levels (≈300 mg/dL). The plasma of Ldlr^−/−Apob^100/100 mice contained large numbers of small lipoproteins, whereas the plasma of Apoe^−/−Apob^100/100 mice contained much lower levels of much larger lipoproteins. Interestingly, the Ldlr^−/−Apob^100/100 mice developed far more extensive atherosclerotic lesions than the Apoe^−/−Apob^100/100 mice. The finding of substantially more atherosclerosis in Ldlr^−/−Apob^100/100 mice than in Apoe^−/−Apob^100/100 mice, despite nearly identical cholesterol levels, suggests that large numbers of small apo B-100–containing lipoproteins are far more atherogenic than lower numbers of large apo B-100–containing lipoproteins.