Abstract: Objective To study the effect of combined simvastatin and ezetimibe on atherosclerosis in ApoE^-/-mice on a high-fat diet. Methods Thirty-six male ApoE^-/-mice aged 8 weeks were randomly divided into model group, simvastatin treatment group and combined simvastatin and ezetimibe treatment group (12 in each group). Animals in simvastatin treatment group were treated with intragastric simvastatin (20 mg/kg), those in combined simvastatin and ezetimibe treatment group were treated with intragastric simvastatin (20 mg/kg) and ezetimibe (10 mg/kg), and those in model group received PBS buffer, once a day for 8 weeks. Aorta tissue sample taken from the animals were stained with oil red O to measure the area of their plaques. Results The serum TG, TC and LDL-C levels were significantly lower in simvastatin treatment group and combined simvastatin and ezetimibe treatment group than in model group (P< 0.01). The serum TG and LDL-C levels were significantly lower in combined simvastatin and ezetimibe treatment group than in simvastatin treatment group (P< 0.01) whereas the HDL-C/LDL-C ratio was significantly higher in combined simvastatin and ezetimibe treatment group than in model group and simvastatin treatment group (P< 0.01). The area of plaques was significantly smaller in simvastatin treatment group and combined simvastatin and ezetimibe treatment group than in model group (P< 0.01). Conclusion Combined simvastatin and ezetimibe inhibits atherosclerosis in ApoE^-/-mice more significantly than simvastatin alone.