Apoe-deficient (Apoe−/−) andLdlr-deficient (Ldlr−/−) mice are two common animal models of hypercholesterolemia and atherosclerosis. The two models differ in lipid and glucose metabolism and other mechanisms involved in atherogenesis. Here we examined atherosclerotic lesion formation in the two models with an atherosclerosis-resistant C3H/HeJ (C3H) background. 3-month-old C3H-Ldlr−/−and C3H-Apoe−/−mice developed minimal atherosclerotic lesions in the aortic root when fed a chow diet. After 12 weeks on a Western diet, C3H-Ldlr−/−mice developed 3-fold larger lesions than C3H-Apoe−/−mice in the aortic root (127,386 ± 13,439 vs. 41,542 ± 5075 μm2/section;p= 0.00028), but neither knockout formed any lesion in the carotid artery. After being ligated near its bifurcation, the common carotid artery developed intimal lesions in both knockouts 4 weeks after ligation, significantly larger in C3H-Ldlr−/−than C3H-Apoe−/−mice (68,721 ± 2706 vs. 47,472 ± 8146 μm2/section;p= 0.028). Compared to C3H-Apoe−/−mice, C3H-Ldlr−/−mice showed a 50% reduction in plasma MCP-1 levels, similar levels of malondialdehyde, an oxidative stress biomarker, on both chow and Western diets, but higher small dense LDL levels on the Western diet. These results suggest a more significant role for small dense LDL than inflammation and oxidative stress in the different susceptibility of the mouse models to atherosclerosis.