The change in tissue uptake clearance of ¹²⁵I-labeled hepatocyte growth factor (HGF) after an intravenous injection of an excess (120 µg/kg) of unlabeled HGF was examined in rats. The heparin-washable component of the hepatic uptake clearance of ¹²⁵I-HGF was only slightly changed, whereas the heparin-resistant component was significantly reduced 30 min after injection of excess HGF, followed by gradual recovery with a half-life of 3.2 h. Because the former clearance mainly represents ¹²⁵I-HGF association with heparan sulfate proteoglycan on the cell surface and/or extracellular matrix, whereas the latter includes relatively specific clearance, such as receptor-mediated endocytosis, this result suggests that injection of excess HGF selectively causes downregulation of receptor-mediated HGF clearance in the liver. Downregulation could also be observed for HGF receptor density in isolated liver plasma membrane, assessed by Western blot analysis by means of anti-receptor antibody, 30 min after injection of excess unlabeled HGF, supporting the hypothesis that the overall elimination of HGF from the systemic circulation can be affected by a change in HGF receptor density on the liver cell surface.