Rabbits fed a 1% cholesterol diet with or without the antioxidant butylated hydroxytoluene (BHT) developed typical atherosclerotic lesions. The addition of BHT gave higher levels of total cholesterol (+40%), triglycerides (+250%), low density lipoprotein (LDL), and very low density lipoprotein (VLDL) in plasma. Despite the lower plasma lipid levels, the degree of atherosclerosis of the aortic surface was considerably higher in rabbits fed cholesterol than in the group treated with cholesterol and BHT. The mean atherosclerotic involvement was 18.6 +/- 4.4% in the former group and 5.9 +/- 1.7% in the latter group (p = 0.02). In all animals, there was a high correlation between the area of the arterial lesion and cholesterol content (r = 0.96). Serum levels of cholesterol autooxidation products (7-ketocholesterol and cholesterol 5 alpha,6 alpha-epoxide) were lower in the group of rabbits treated with BHT (p less than 0.005). Serum levels of vitamin E were slightly higher in the BHT group. There was no significant difference in the clearance of beta-VLDL between the two treatment groups after using either beta-VLDL from cholesterol-fed animals or beta-VLDL from BHT-fed animals. The results are in accord with the contention that oxidative modification of lipoproteins is important for the development of atherosclerosis and that antioxidants may have a protective effect. At present, however, other explanations cannot be completely excluded, for example, effects of antioxidants on immunologic factors or monocyte adhesion.