The contribution of lipid lowering in protection against adriamycin cardiomyopathy achieved by probucol, an antioxidant and a lipid-lowering drug, was assessed by comparing its beneficial effects with that of lovastatin, another lipid-lowering drug with no known antioxidant properties. Adriamycin (cumulative dose, 15 mg/kg body weight) was given to rats in 6 equal injections (intraperitoneally) over a period of 2 weeks. Probucol (cumulative dose, 120 mg/kg body weight) or lovastatin (cumulative dose, 48 mg/kg body weight) was given in 12 equal injections (intraperitoneally) before and concurrent with adriamycin. After 3 weeks of post-treatment with adriamycin, congestive heart failure, ascites, congested liver, and depressed cardiac function were seen. Adriamycin treatment decreased glutathione peroxidase activity and increased lipid peroxidation. Adriamycin increased plasma triglycerides, total cholesterol, and high- and low-density lipoproteins. Myocardial triglycerides and total cholesterol were also increased. Probucol completely prevented the development of congestive heart failure and normalized myocardial and plasma triglycerides and total cholesterol, and significantly decreased plasma high- and low-density lipoproteins. Lovastatin significantly attenuated but did not completely prevent cardiomyopathic changes due to adriamycin. Lovastatin decreased plasma total cholesterol and low-density lipoproteins as well as myocardial triglycerides and total cholesterol. Plasma triglycerides and high-density lipoproteins were still high in the adriamycin plus lovastatin group. Probucol improved glutathione peroxidase activity and reduced lipid peroxidation whereas lovastatin had no effect on these adriamycin-induced changes. These data suggest that adriamycin cardiomyopathy is associated with an antioxidant deficit as well as increased myocardial and plasma lipids. Complete protection by probucol against adriamycin-induced congestive heart failure may be due to the unique combination of its antioxidant and lipid-lowering properties.