In a recent study of IFN-γ 1b in 330 patients with idiopathic pulmonary fibrosis (IPF), progression-free survival was unchanged; however, a trend toward lower mortality was seen in IFN-γ 1b-treated patients compared with placebo-treated patients (9.9 vs. 16.7%; p = 0.08). The purpose of this randomized, double-blind, placebo-controlled trial was to characterize molecular effects of subcutaneous IFN-γ 1b (200 μg) thrice weekly for 6 months versus placebo in 32 patients with IPF. Messenger RNA in transbronchial lung biopsies and bronchoalveolar lavage cell pellet and protein levels in bronchoalveolar lavage fluid (BALF) and plasma were evaluated. After IFN-γ 1b treatment, IFN-inducible T cell-α chemoattractant/CXCL11 (a chemokine with immunomodulatory, antiangiogenic, and defensin-like antimicrobial properties) increased in BALF (p = 0.016) and plasma (p < 0.001); BALF levels of epithelial neutrophil-activating protein-78/CXCL5 (p = 0.054), platelet-derived growth factor A (p = 0.033), and Type I procollagen (p = 0.096) were lower; and IFN-γ levels were higher (p = 0.093) versus placebo. For messenger RNA in transbronchial biopsies, trends (p > 0.05 and ≤ 0.10) associated with IFN-γ 1b treatment included an increase in IFN-inducible T cell-α chemoattractant/CXCL11, a decrease in elastin, and smaller increases for Type III procollagen and platelet-derived growth factor B. Changes in biomarkers of fibrosis, angiogenesis, proliferation, immunomodulation, and antimicrobial activity suggest that IFN-γ 1b may affect IPF through multiple pathways.