After pneumonectomy, the remaining lung increases in size. This process is referred to as compensatory lung growth. Various pathways likely play important roles in this growth response. The molecular mechanisms involved in compensatory lung growth, however, remain poorly understood. Hypoxia-induced mitogenic factor (HIMF), also called FIZZ1 or RELM-alpha, possesses mitogenic, vasoconstrictive, angiogenic, and antiapoptotic effects. In this study, we examined the expression of HIMF in mouse lung after pneumonectomy to test the hypothesis that HIMF expression is upregulated during compensatory lung growth. Results showed that HIMF is upregulated from Day 1 after pneumonectomy and peaking at Day 7 in the lung. HIMF upregulation is temporally and spatially related to lung cell proliferation, as demonstrated by expression of proliferating cell nuclear antigen. Immunohistochemical staining and in situ hybridization showed that upregulated HIMF protein and mRNA are mainly distributed in airway epithelium, alveolar type II cells, and endothelial cells of the pulmonary vessels. Intratracheal instillation of recombinant HIMF resulted in widespread cell proliferation, including airway epithelium, alveolar type II cells, and cells in the alveolar septa. These results indicate a new role for HIMF in compensatory lung growth, which is that HIMF may act as a lung-specific growth factor and participate in lung regeneration after pneumonectomy.