Considerable evidence indicates that hyperglycemia increases oxidative stress and contributes to the increased incidence of atherosclerosis and cardiovascular complications in diabetic patients. To examine the effect of α-lipoic acid, a potent natural antioxidant, on atherosclerosis in diabetic mice, 3-month-old apolipoprotein (apo) E-deficient (apoE−/−) mice were made diabetic by administering streptozotocin (STZ). At 4 weeks after starting the STZ administration, a high-fat diet with or without α-lipoic acid (1.65 g/kg) was given to the mice and to nondiabetic apoE−/− controls. At 20 weeks, markers of oxidative stress were significantly lower in both the diabetic apoE−/− mice and their nondiabetic apoE−/− controls with α-lipoic acid supplement than in those without it. Remarkably, a-lipoic acid completely prevented the increase in plasma total cholesterol, atherosclerotic lesions, and the general deterioration of health caused by diabetes. These protective effects of α-lipoic acid were accompanied by a reduction of plasma glucose and an accelerated recovery of insulin-producing cells in the pancreas, suggesting that part of its effects are attributable to protecting pancreatic в-cells from damage. Our results suggest that dietary α-lipoic acid is a promising protective agent for reducing cardiovascular complications of diabetes.