Although it is known that the lung undergoes compensatory growth after pulmonary resection, mechanisms by which lung cells exhibit compensatory proliferation are not well defined. We investigated the involvement of hepatocyte growth factor (HGF) in postpneumonectomy compensatory lung regeneration in mice, because HGF has mitogenic and morphogenic actions on lung epithelial cells. Following left pneumonectomy, alveolar and airway epithelial cells underwent compensatory DNA synthesis, reaching maximal levels 5 d after the surgery. Before changes in DNA synthesis in lung epithelial cells, expression of HGF mRNA and protein levels in the remaining lung, liver, and kidney were changed in response to left pneumonectomy, and these changes were associated with postoperative increases in plasma HGF levels. c-Met/HGF receptor expression was localized predominantly in alveolar type II and airway epithelial cells, whereas c-Met/HGF receptor mRNA expressions were transiently upregulated before the peak in lung DNA synthesis. Neutralization of endogenous HGF by an antibody in pneumonectomized mice suppressed the compensatory DNA synthesis in lung epithelial cells, whereas administration of recombinant HGF to pneumonectomized mice stimulated DNA synthesis in lung epithelial cells. These results strongly suggest that HGF has a role as a pulmotrophic factor in postpneumonectomy compensatory lung regeneration.