Diabetes mellitus is one of the major risk factors for atherosclerosis. In recent years several murine models have been developed in an attempt to reproduce the accelerated atherosclerosis by combining induced hyperglycemia with hyperlipidemia. In the present study we wished to examine the effect of spontaneous hyperglycemia and hyperlipidemia induced by high fat diet on atherosclerosis development and on markers of the immune system in diabetes prone NOD mice. We tested two high fat dietary regimens (with or without cholate supplementation) in female NOD mice that either developed or did not develop diabetes. Plasma fasting glucose, lipid profile, antibodies to oxidized-LDL and glycated-LDL were assessed. The spleens from both groups were evaluated for their proliferative response. The extent of atherosclerosis was assessed at the aortic sinus. It was found that the two high fat dietary regimens were insufficient to elicit atherosclerosis in the diabetic and non-diabetic NOD mice. The diabetic hyperlipidemic NOD mice displayed an increased cellular immune response to glycated-LDL in comparison with their non-diabetic littermates. The immune response towards copper oxidized LDL was similar in both groups despite an increased susceptibility of LDL extracted from diabetic hyperlipidemic mice to undergo copper induced oxidation. We conclude that the NOD mouse is highly resistant to atherosclerosis even in the presence of hyperglycemia-hyperlipidemia and increased susceptibility to copper induced LDL oxidation.