Abstract: AIM:To study the protective effects of atorvastatin on hyperhomocysteinemia (HHcy)-induced atherosclerosis and possible mechanisms. METHODS: Seven-week-old male ApoE-/- mice were fed with 20 g/L L-methionine for 3 months to establish an atherosclerosis plaque model with HHcy. In the divided groups (without or with atorvastatin pretreatment for 1 month), plasma Hcy levels were measured by high-performance liquid chromatography. Aortic roots were isolated for morphologic pathology and immunohistochemistry and TUNEL analysis were conducted to investigate the apoptosis index in the lesion. Aortic ROS production was measured by nitroblue tetrazolium (NBT) formazan and lucigenin-enhanced chemiluminescence, aortic NADPH oxidase activity was evaluated with lucigenin-enhanced chemiluminescence, and NADPH oxidase 4 (Nox4) was evaluated with Western blot. RESULTS: Three-month high methionine diet induced the formation of atherosclerosis plaque in the aorta of ApoE-/- mice accompanied by an increase of Hcy in plasma. Administration of atorvastatin for 1 month reduced plasma Hcy level, suppressed development of atherosclerosis plaque, inhibited apoptosis in atherosclerosis plaque and NBT formazan deposit, and decreased ROS formation, NADPH oxidase activation and Nox4 expression in the vessel wall. CONCLUSION: Atorvastatin attenuates HHcy-induced atherosclerosis in ApoE-/- mice. Its mechanism may be related to the inhibition of Nox4-derived oxidative stress and the subsequent decrease of apoptosis of endothelial cells.