High glucose plays an important role in the pathogenesis of atherosclerosis. In this study, we assessed the effects of high glucose on human umbilical vein endothelial cell (HUVEC) apoptosis. Additionally, we investigated whether α-lipoic acid, an antioxidant, prevents high glucose-induced apoptosis of HUVECs. HUVECs were treated with high glucose in the presence or absence of α-lipoic acid. Treatment of HUVECs with high glucose changed cell morphology and induced DNA fragmentation, leading to apoptosis. Apoptosis was induced by high glucose in a dose-and time-dependent fashion. High glucose markedly elevated Bax, and decreased NF-κB and Bcl-2 expression. Most importantly, pretreatment with α-lipoic acid protected against high glucose-induced apoptosis in the endothelial cells. α-Lipoic acid significantly promoted the expression of NF-κB while decreasing the expression of Bax and the activities of caspase-3 and-9 without significantly affecting the Bcl-2 level. Our data suggest that high glucose induces apoptosis in endothelial cells. α-Lipoic acid effectively attenuates high glucose-induced endothelial cell apoptosis. These findings provide new perspectives on the role of α-lipoic acid in cardiovascular disease.