Diabetes mellitus is one of the major risk factors associated with atherosclerosis and coronary heart disease but the mechanistic links between the disease and atherosclerosis are not well understood. In this study, we investigated the effect of the deletion of the long-form leptin receptor on the progression of atherosclerosis in ApoE-/- mouse. ApoE-/-;db/db double knockout mice as well as ApoE-/-;db/+ and ApoE-/- littermates were generated by crossing ApoE-/- and db/+ mice. On a regular chow diet, ApoE-/-;db/db mice at 20 weeks of age exhibited features typical of type 2 diabetes: obesity, hyperglycemia, hyperinsulinemia and dyslipidemia and had significantly accelerated atherosclerosis compared with their age-matched ApoE-/- littermates as assessed by either the percentage of the aorta bearing lesion (5.3+/-0.9% for ApoE-/-;db/db versus 1.5+/-0.5% for ApoE-/-) or by aortic lipid content ( approximately 1.5-2-fold increase in free cholesterol and approximately 3-4-fold increase in cholesteryl ester). The atherosclerosis in these ApoE-/-;db/db mice was further accelerated by feeding mice with a Western diet and markedly inhibited by fenofibrate with a 2.5- and 5.3-fold reduction of the lesion in male and female mice, respectively. The results from this study demonstrate that type 2 diabetes can accelerate atherogenesis in mice. This mouse model may provide insight into the mechanistic link between type 2 diabetes and atherosclerosis as well as serve as a valuable tool for evaluating therapeutics.