The purpose of this study was to investigate the effect of a high-methionine plus cholesterol diet (HM+HC) on plasma, erythrocyte, liver and aorta lipid, lipid peroxide levels, and the liver antioxidant system, as well as hepatic and aortic histopathology in C57BL/6J mice, and to compare these results to those observed following administration of a high-methionine (HM) or high-cholesterol diet, (HC) alone. Mice were fed diets containing 1.5% methionine, 1.5% cholesterol and 0.5% cholic acid, or a combination of the two diets, for 4 mo. The HM diet did not alter cholesterol or diene conjugate (DC) levels in the plasma or aorta, but this diet caused increases in cholesterol, triglyceride, malondialdehyde (MDA) and DC levels and a decrease in a-tocopherol levels without any change in the levels of glutathione and ascorbic acid or the activities of superoxide dismutase, glutathione peroxidase and glutathione transferase in the liver of mice. However, the HC diet alone was found to further increase cholesterol, triglyceride, MDA and DC levels in the plasma and liver together with changes in hepatic antioxidant system elements, but aortic cholesterol and DC levels remained unchanged as compared to the control group. There were no changes in blood hemoglobin and erythrocyte MDA levels or erythrocyte hemolysis values in both the HM and HC groups. However, the parameters related to lipid and lipid peroxide and antioxidant systems did not change in the plasma or tissues of the HM+HC and HC groups. Only plasma cholesterol was observed to increase in the HM+HC group as compared to the HC group. In addition, histopathological findings in the liver and aorta were similar in the HC and HM+HC groups. In conclusion, our results indicate that the addition of methionine to the HC diet did not augment oxidative stress, hepatotoxicity or atherosclerotic changes induced by the HC diet in mice.