Rationale: An increase in the number of mononuclear phagocytes in lung biopsies from patients with idiopathic pulmonary fibrosis (IPF) worsens prognosis. Chemokines that recruit mononuclear phagocytes, such as CCL2, are elevated in bronchoalveolar lavage (BAL) fluid from patients with IPF. However, little attention is given to the role of the mononuclear phagocyte survival and recruitment factor, macrophage colony-stimulating factor (M-CSF), in pulmonary fibrosis. Objective: To investigate the role of mononuclear phagocytes and M-CSF in pulmonary fibrosis. Methods: Wild-type, M-CSF (-/-), or CCL2 (-/-) mice received intra-peritoneal bleomycin. Lung inflammation and fibrosis were measured by immunohistochemistry, ELISA, collagen assay, BAL differentials, Real-Time PCR, and Western blot analysis. Human and mouse macrophages were stimulated with M-CSF for CCL2 expression. BAL fluid from IPF patients was examined for M-CSF and CCL2. Measurements and Main Results: M-CSF (-/-) and CCL2 (-/-) mice had less lung fibrosis, mononuclear phagocyte recruitment, collagen deposition, and connective tissue growth factor (CTGF) expression following bleomycin administration than wild-type littermates. Human and mouse macrophages stimulated with M-CSF had increased CCL2 production, and intra-tracheal administration of M-CSF in mice induced CCL2 production in BAL fluid. Finally, BAL fluid from patients with IPF contained significantly more M-CSF and CCL2 than BAL fluid from normal volunteers. Elevated levels of M-CSF were associated with elevated CCL2 in BAL fluid and the diagnosis of IPF. Conclusions: These data suggest that M-CSF contributes to the pathogenesis of pulmonary fibrosis in mice and in patients with IPF through the involvement of mononuclear phagocytes and CCL2 production.