Initial binding and subsequent endocytosis of small and large chylomicron remnants by rat liver were compared. Small and large chylomicrons were obtained from mesenteric lymph of glucose- or fat-fed rats, respectively. The low-density lipoprotein (LDL) receptor was up- and down-regulated as shown by LDL receptor messenger RNA (mRNA). The rate of removal of small chylomicron remnants by isolated perfused rat livers followed closely the activity of the LDL receptor. When mRNA was undetectable, the uptake was as low as that of lymphatic small chylomicrons. In contrast, the uptake of large chylomicron remnants into perfused rat livers was unaffected by changes of the LDL-receptor activity, but significantly reduced after livers were flushed with heparin or heparinase. Large chylomicron remnants were cleared from plasma much faster than small chylomicron remnants, but were more slowly internalized into hepatocytes. Both, small and large chylomicron remnants entered the pathway of receptor-mediated endocytosis as shown by electron microscopy and analysis of isolated endosomes. Yet, large chylomicron remnants were taken up into the compartment of uncoupling of receptors and ligands and multivesicular bodies at a much slower rate. This was independent of the activity of the LDL receptor and the heparin-releasable binding site. From these findings it is concluded that large chylomicron remnants initially bind rapidly to surface components other than the LDL receptor, one of which may be hepatic lipase. Yet, the consecutive internalization is slow. In contrast, small chylomicron remnants are removed at a slower rate from plasma, binding predominantly to the LDL receptor, but are more readily taken up into endosomes.