Background. Diabetes is associated with increased cardiovascular disease, but the underlying cellular and molecular mechanisms are poorly understood. One proposed mechanism is that diabetes aggravates atherosclerosis by enhancing plaque inflammation. TheAkitamouse has recently been adopted as a relevant model for microvascular complications of diabetes. Here we investigate the development of atherosclerosis and inflammation in vessels ofAkitamice onLDLr−/−background.Methods and Results.Akita-LDLr−/−andLDLr−/−mice were fed high-fat diet from 6 to 24 weeks of age. Blood glucose levels were higher in both male and femaleAkita-LDLr−/−mice (137% and 70%, resp.). MaleAkita-LDLr−/−mice had markedly increased plasma cholesterol and triglyceride levels, a three-fold increase in atherosclerosis, and enhanced accumulation of macrophages and T-cells in plaques. In contrast, femaleAkita-LDLr−/−mice demonstrated a modest 29% increase in plasma cholesterol and no significant increase in triglycerides, atherosclerosis, or inflammatory cells in lesions. MaleAkita-LDLr−/−mice had increased levels of plasma IL-1βcompared to nondiabetic mice, whereas no such difference was seen between female diabetic and nondiabetic mice.Conclusion.Akita-LDLr−/−mice display considerable gender differences in the development of diabetic atherosclerosis. In addition, the increased atherosclerosis in maleAkita-LDLr−/−mice is associated with an increase in inflammatory cells in lesions.