We have previously shown that bile duct ligation inhibits the hepatic uptake of chylomicron remnants in rats. In the present study we have investigated different possible causes of this inhibition. Intravenous infusion of bile or sodium taurocholate reduced the hepatic chylomicron remnant uptake. Perfused livers from bile duct-ligated rats metabolized chylomicron remnants at a reduced rate. Rat hepatocyte monolayer cultures metabolized remnants formed in cholestatic rats and those formed in hepatectomized animals equally well, but serum from cholestatic rats inhibited remnant uptake more strongly than control serum. Bile duct ligation did not influence the clearance from plasma of human low-density lipoprotein, and the inhibition of hepatic remnant uptake was not affected by treatment of cholestatic rats with ethinylestradiol. The clearance of 125I-labeled asialofetuin was only slightly impaired by cholestasis, indicating that no strong inhibition of all endocytic processes of the hepatocytes occurred. The reduced hepatic uptake of chylomicron remnants in the cholestatic rat is thus not due to formation of abnormal remnant particles. An increased plasma bile acid concentration rapidly reduced the hepatic remnant uptake without causing any significant hyperlipidemia. However, the pathological lipoproteins accumulating in the cholestatic rat aggravated the hepatic uptake defect even further.