Apo-E–deficient apo-B100–only mice (Apoe^–/–Apob^100/100) and LDL receptor–deficient apo-B100–only mice (Ldlr^–/–Apob^100/100) have similar total plasma cholesterol levels, but nearly all of the plasma cholesterol in the former animals is packaged in VLDL particles, whereas, in the latter, plasma cholesterol is found in smaller LDL particles. We compared the apo-B100–containing lipoprotein populations in these mice to determine their relation to susceptibility to atherosclerosis. The median size of the apo-B100–containing lipoprotein particles in Apoe^–/–Apob^100/100 plasma was 53.4 nm versus only 22.1 nm in Ldlr^–/–Apob^100/100 plasma. The plasma levels of apo-B100 were three- to fourfold higher in Ldlr^–/–Apob^100/100 mice than in Apoe^–/–Apob^100/100 mice. After 40 weeks on a chow diet, the Ldlr^–/–Apob^100/100 mice had more extensive atherosclerotic lesions than Apoe^–/–Apob^100/100 mice. The aortic DNA synthesis rate and the aortic free and esterified cholesterol contents were also higher in the Ldlr^–/–Apob^100/100 mice. These findings challenge the notion that all non-HDL lipoproteins are equally atherogenic and suggest that at a given cholesterol level, large numbers of small apo-B100–containing lipoproteins are more atherogenic than lower numbers of large apo-B100–containing lipoproteins.