Monocyte chemotactic protein-3 (MCP-3), a chemokine that is in a superfamily of structurally related small chemotactic cytokines involved in leukocyte trafficking, is regarded as a key factor in atherogenesis. In this study, we examined the changes in atherogenic parameters including hepatic lipid accumulation and oxidative balance in MCP- 3-overexpressing transgenic mice (MCP-3 mice) under atherogenic conditions. To induce an extreme atherogenic condition, mice were fed a high-fat, high-cholesterol (HFHC) diet for 12 weeks. The body weight and food intake were not changed by MCP-3 overexpression in the aorta. On a HFHC diet, the MCP-3 mice had higher plasma levels of total cholesterol and a higher atherogenic index compared with wild-type mice, although there were no differences in the plasma HDL-cholesterol and triglyceride levels. Furthermore, an increase in lipid accumulation was observed in the aortas as well as the livers of the HFHC diet-fed MCP-3 mice compared with wild-type mice. The activities of antioxidant enzymes increased in the livers of the HFHC diet-fed MCP-3 mice, whereas supplementation with antioxidants, naringin and hesperidin, reversed the activities of the hepatic antioxidant enzymes in HFHC diet-fed MCP-3 mice, indicating that there might be more oxidative damage to the tissues in the HFHC diet-fed MCP-3 mice leading to progression towards atherosclerosis and hepatic steatosis. Microarray analyses of the aorta revealed atherosclerosis-, PPARs-, lipoprotein receptor, and apolipoprotein-related genes that were affected by the HFHC diet in MCP-3 mice. These findings suggest that aortic MCP-3 overexpression may contribute to the development of atherosclerosis and hepatic steatosis under atherogenic conditions.