Ischemia and reperfusion (I/R) injuries occur in numerous organs under pathophysiological conditions. In this process, neutrophils play important roles in eliciting parenchymal injuries. Using a murine model of renal I/R, we show that hepatocyte growth factor (HGF) is a natural ligand that inhibits endothelial injuries and neutrophil extravasation. In mice after renal I/R, plasma HGF levels increased, along with c-Met/HGF receptor phosphorylation in the vascular endothelium. However, this c-Met activation was transient, associated with a decrease in endogenous HGF level, and followed by neutrophil infiltration and renal dysfunction. Suppression of endothelial c-Met phosphorylation by anti-HGF IgG led to rapid progressions of neutrophil extravasation, tubular apoptosis, and renal dysfunction. Inversely, enhancement of the c-Met activation by exogenous HGF blocked endothelial/tubular apoptotic injuries and acute renal failure. In this process, HGF prevented endothelial nuclear factor kappaB activation and inhibited induction of an adhesion molecule (ICAM-1), resulting in attenuated vascular edema and neutrophil infiltration. Thus, we conclude that 1) the HGF/c-Met system of endothelial cells confers an initial barrier to block neutrophil infiltration, and 2) transient and insufficient HGF production allows manifestation of postischemic renal failure. Our study provides a rationale for why HGF supplementation elicits therapeutic effects in ischemic kidneys.