The present study was aimed at clarifying the uptake mechanisms of fractionated 3H-heparin (FH) in rat liver parenchymal cells in an effort to explore further the clinical applications of mucopolysaccharides, including their utilization in drug delivery. The internalization and surface binding of FH were determined by removing surface-bound FH by the NaCl wash method in uptake experiments in rat liver parenchymal cells in primary culture. Initial and transient peaks were observed in the time course of the surface binding of FH, suggesting the involvement of receptor-mediated endocy tosis (RME) and downregulation of the receptors. Consistent with this suggestion, internalization of FH was reduced by lowering the temperature from 37 to 4°C, while total association was unchanged. Although the internalization of FH was slow and concentration independent, both total association and internalization were inhibited by ligands of the scavenger receptor and some anions, but not by inhibitors of the RME of polypeptides. All these results collectively suggest the involvement of the scavenger receptor or similar substance in terms of substrate specificity in the uptake of FH in rat liver parenchymal cells. This is the first suggestion of the existence of the scavenger-like receptor in liver parenchymal cells. Macromolecular compounds such as heparin have recently been increasingly investigated for their clinical applications, including utilization as carriers for drug delivery (Nishikawa et al. 1995). Although there have been a number of studies concerning the disposition of polypeptides in the body and the utilization of macromolecules as drug carriers, more extensive studies are required to exploit a variety of macromolecules for clinical applications. Heparin, a macromolecular drug with molecular weights ranging from 3000 to 30,000 d., has been used as an anticoagulant drug. The disposition of heparin after intravenous administration depends on the molecular weight