Background: M2-like/repair macrophages are thought to contribute to fibrotic process of idiopathic pulmonary fibrosis (IPF). We analyzed the association between pulmonary accumulation of M2-like macrophages and survival in IPF patients. Methods: Lung tissues were obtained by surgical lung biopsy from patients with IPF (n=16), nonspecific interstitial pneumonia (NSIP, n=8) and control subjects (n=14). Samples were also obtained at autopsy from 9 patients who died of acute exacerbation (AE) of IPF. Lung specimens and/or human peripheral blood mononuclear cells-derived macrophages were evaluated by immunohistochemistry for expression of CD68 (pan-macrophage marker), CD163, and CD204 (M2-like macrophage markers), and by in situ mRNA hybridization and ELISA for production of transforming growth factor-β1 (TGF-β1). Results: CD68⁺, CD163⁺, and CD204⁺ cell counts and CD163⁺/CD68⁺ and CD204⁺/CD68⁺ cell ratios were comparable in IPF and NSIP lung tissues and significantly higher than in control tissues. IPF-AE lung samples contained significantly elevated CD68⁺ and CD163⁺ cell counts and CD163⁺/CD68⁺ cell ratio compared with IPF samples, whereas CD204⁺ cell counts and CD204⁺/CD68⁺ cells ratio did not differ. High CD163⁺/CD68⁺ and CD204⁺/CD68⁺ cell ratios were significantly associated with shorter overall survival and time-to-AE in IPF patients. In vitro-differentiated human CD163⁺ and CD204⁺ macrophages both secreted TGF-β1; however, the novel IPF drug pentraxin 2/serum amyloid protein could suppress secretion only by CD204⁺ macrophages. Conclusions: Pulmonary accumulation of CD163⁺ and CD204⁺ macrophages is associated with worse clinical course in IPF patients. Suppression of macrophage activation and TGF-β1 secretion may be a potential therapeutic target for IPF.