Modulation of the activities of drug-metabolizing enzymes by dietary cholesterol was studied in rabbits. In male rabbits fed a 1.5% cholesterol-diet, an elevated levels of serum cholesterols and triglycerides were observed from the early phase of cholesterol-feeding. At 12 weeks after the onset of cholesterol feeding, a marked increase was observed in the wet weights of livers but not of lungs, while total contents of lipids and cholesterols were elevated in both tissues in cholesterol-fed animals. The content of collagen was increased significantly in livers, but not in lungs and the phase I drug-metabolizing enzyme activities were significantly reduced in livers but remained unchanged in lungs by cholesterol feeding. On the other hand, the phase II drug-metabolizing enzyme activities varied depending on the enzymes in both tissues. The results demonstrate that dietary cholesterol induces different effects on rabbit liver and lung and that the modulation of the hepatic enzymes by dietary cholesterol in rabbits differs from that in rats, mice and guinea pigs in which the activity of the enzymes are elevated by dietary cholesterol.