γ-Tocopherol, produced by many plants, is the major form of tocopherol in the United States diet. It is an effecient protector of lipids against peroxidative damage. Epidemiologic studies show that supplementation of diet with γ-tocopherol is inversely related to the risk of death from cardiovascular disease. This study was conducted to examine the role of γ-tocopherol in oxidized LDL (ox-LDL)-induced nuclear factor (NF)-κB activation and apoptosis in human coronary artery endothelial cells (HCAECs). Cultured HCAECs were treated with ox-LDL (10-40 μg/ml). Incubation of HCAECs with ox-LDL resulted in apoptosis of HCAECs, as determined by TUNEL and DNA laddering. Ox-LDL degraded IκB protein and activated NF-κB in HCAECs (bothP< 0.01 vs control), as determined by Western blot. Treatment of cells with γ-tocopherol attenuated ox-LDL-mediated degradation of IκB and activation of NF-κB (bothP< 0.01 vs ox-LDL alone). The presence of γ-tocopherol also reduced ox-LDL-induced apoptosis (P< 0.01 vs ox-LDL alone). A high concentration of γ-tocopherol (50 μmol/L) was more effective than the low concentration of γ-tocopherol (10 μmol/L) in this process. These observations show that ox-LDL induces apoptosis of HCAECs at least partially by activation of NF-κB signal transduction pathway. γ-Tocopherol significantly decreases ox-LDL-induced apoptosis of HCAECs by inhibiting the activation of NF-κB.