Three models of hypercholesterolemia in rabbits were positively associated with plasma cholesteryl ester and triglyceride transfer activities. In cholesterol-fed rabbits, the transfer activities increased two- to three-fold when plasma cholesterol concentration reached about 1500 mg/dl. In hypercholesterolemia induced by feeding a cholesterol-free semisynthetic casein-sucrose diet, plasma cholesterol increased up to three-fold and the increase in cholesteryl ester and triglyceride transfer activities per unit of plasma cholesterol increment was similar to that in cholesterol-fed rabbits. Watanabe heritable hyperlipidemic rabbits, in which hypercholesterolemia is induced by a genetic defect of the LDL receptor, had significantly higher transfer activities than normolipidemic rabbits. However, fasting, which also induced hypercholesterolemia, lowered transfer activities, whereas refeeding returned them to prefasting levels. In rats, hypercholesterolemia induced by a high cholesterol diet did not increase cholesteryl ester and triglyceride transfer activities. Although hypercholesterolemia in rabbits may not be the primary cause of increased lipid transfer activities, some mechanism related to hypercholesterolemia appears to be associated with increased cholesteryl ester and triglyceride transfer activities.