Adipophilin is a specific marker for lipid accumulation in a variety of cells and for diseases associated with fat-accumulating cells. Lipid-laden foam cells derived from macrophages play a critical role in the development of atherosclerosis. By immunohistochemistry with specific monoclonal antibody, it was shown that expression of adipophilin is induced by high-cholesterol-diet feeding in rabbit atherosclerotic lesions. New Zealand white rabbits were fed with high cholesterol chow for 12 weeks. The level of serum total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglyceride, and cholesterol content of aortic wall was investigated. The areas of fatty streak of the aortas was measured after staining with SudanⅣ. The aortic, and liver specimens with HE and immunohistochemistry staining were observed with light microscopes. The level of serum total cholesterol, low density lipoprotein cholesterol, and cholesterol of aortic wall was significantly increased and the areas of fatty streak of the aortas was (40.06±7.29)% at the end of 12-week-cholesterol feeding. The fatty streak of the aorta with immunohistochemistry staining was strongly positive for adipophilin in animals fed with high cholesterol chow, and the liver was negative with or without high cholesterol chow. Antisense oligodeoxynucleotides of mouse adipophilin was also constructed, mouse peritoneum macrophages was cultured with oxLDL or oxLDL plus the antisense fragment. The results showed that adipophilin antisense decreased cellular cholesterol and lipid droplet content of the cell. The data suggested that the expression of adipophilin in vessel walls is related to the hypercholesterolemia, and has a potential role in lipid accumulation in macrophages and pathogenesis of atherosclerosis.