Oxidative stress has been proposed to be a major cause of atherosclerosis in diabetes. Endothelial dysfunction, common in diabetes, is considered a prerequisite for atherosclerosis. We evaluated whether alpha-lipoic acid (ALA) is an effective treatment for oxidative stress-induced endothelial dysfunction. Using high resolution ultrasound techniques, we evaluated flow mediated vasodilation (FMD) of the brachial artery in 13 young healthy men with transient hypertriglyceridemia (HTG) induced by intralipid infusion and in 11 postmenopausal type 2 diabetics before and after ALA treatment. We also measured superoxide anion formation in neutrophils as a maker of oxidative stress. FMD was decreased and superoxide anion formation was increased significantly following intralipid infusion in the young healthy men. ALA treatment, however, reversed the HTG-induced endothelial dysfunction and decreased the superoxide anion formation. Similarly, treatment with ALA increased FMD and decreased superoxide anion formation in the postmenopausal type 2 diabetics. In addition, the change in FMD was negatively correlated with superoxide anion formation in young healthy men and in postmenopausal type 2 diabetics (r = -0.54, -0.65, respectively). All P values were below 0.05. In conclusion, our results demonstrate that ALA treatment improves HTG- and diabetic-induced endothelial dysfunction, possibly due to the antioxidant effect of ALA.