Objective: To investigate the mechanisms that Simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A(HMG-CoA) reductase inhibitor, plays an important role in primary prevention of atherosclerosis independently of its lipid-lowering effect in Apolipoprotein E-deficient mice in the early stage of atherosclerosis. Methods: Twenty-four 6-week old male apoE-deficient mice were randomly divided into two groups:control group(normal saline) and treatment group[simvastatin(5 mg/(kg·d))]. Simvastatin was administered to treatment group mice by gavage and the same volume of normal saline was administered to control group mice by the same method for 2 or 4 weeks.Total cholesterol(TC), super-oxide dismutase(SOD), malondialdehyde(MDA) and serum nitric oxide(NO) were measured by bio-chemical analysis. Results: There was no significant difference in serum TC between control and treatment groups. Compared with the control’s, the effects of simvastatin were more significant in decreasing serum MDA level(P < 0.01 vs control’s at 2-week; P < 0.006 vs control’s at 4-week), increasing serum SOD level(P < 0.03 vs control’s at 2-week; P < 0.003 vs control’s at 4-week) and NO level(P < 0.01 control’s at 2-week; P < 0.001 vs control’s at 4-week) either at 2 or 4 weeks. Conclusion: Simvastatin attenuates oxidative stress and protects endothelial function by the mechanisms of decreasing serum MDA level, increasing serum SOD level and NO level , which were inconsistent with its cholesterol-lowering effect. It may play an important role in primary(if not all) prevention of atherosclerosis and might be independent of lipid-regulation mechanism.