—The role of insulin resistance (IR) in atherogenesis is poorly understood, in part because of a lack of appropriate animal models. We assumed that fructose-fed LDL receptor-deficient (LDLR^−/−) mice might be a model of IR and atherosclerosis because (1) fructose feeding induces hyperinsulinemia and IR in rats; (2) a preliminary experiment showed that fructose feeding markedly increases plasma cholesterol levels in LDLR^−/− mice; and (3) hypercholesterolemic LDLR^−/− mice develop extensive atherosclerosis. To test whether IR could be induced in LDLR^−/− mice, 3 groups of male mice were fed a fructose-rich diet (60% of total calories; n=16), a fat-enriched (Western) diet intended to yield the same plasma cholesterol levels (n=18), or regular chow (n=7) for approximately 5.5 months. The average cholesterol levels of both hypercholesterolemic groups were similar (849±268 versus 964±234 mg/dL) and much higher than in the chow-fed group (249±21 mg/dL). Final body weights in the Western diet group were higher (39±6.2 g) than in the fructose- (27.8±2.7 g) or chow-fed (26.7±3.8 g) groups. Contrary to expectation, IR was induced in mice fed the Western diet, but not in fructose-fed mice. The Western diet group had higher average glucose levels (187±16 versus 159±12 mg/dL) and 4.5-fold higher plasma insulin levels. Surprisingly, the non–insulin-resistant, fructose-fed mice had significantly more atherosclerosis than the insulin-resistant mice fed Western diet (11.8±2.9% versus 7.8±2.5% of aortic surface; P<0.01). These results suggest that (1) fructose-enriched diets do not induce IR in LDLR^−/− mice; (2) the Western diets commonly used in LDLR^−/− mice may not only induce atherosclerosis, but also IR, potentially complicating the interpretation of results; and (3) IR and hyperinsulinemia do not enhance atherosclerosis in LDLR^−/− mice, at least under conditions of very high plasma cholesterol levels. The fact that various levels of hypercholesterolemia can be induced in LDLR^−/− mice by fat-enriched diets and that such diets induce IR and hyperinsulinemia suggest that LDLR^−/− mice may be used as models to elucidate the effect of IR on atherosclerosis, eg, by feeding them Western diets with or without insulin-sensitizing agents.