Rationale: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with no known efficacious therapy. Imatinib is a tyrosine kinase inhibitor with potential efficacy to treat fibrotic lung disease. Objectives: To investigate the safety and clinical effects of imatinib in patients with IPF. Methods: We studied 119 patients in an investigator-initiated, multicenter, multinational, double-blind clinical trial to receive imatinib or placebo for 96 weeks. Measurements and Main Results: Over 96 weeks of follow-up, imatinib did not differ significantly from placebo (log rank P = 0.89) for the primary endpoint defined as time to disease progression (10% decline in percent predicted FVC from baseline) or time to death. There was no effect of imatinib therapy on change in FVC at 48, 72, or 96 weeks (P ≥ 0.39 at all time points) or change in diffusing capacity of carbon monoxide at 48, 72, or 96 weeks (P ≥ 0.26 at all time points). Change in resting PaO2 favored imatinib therapy at 48 weeks (P = 0.005) but not at 96 weeks (P = 0.074). During the 96-week trial there were 8 deaths in the imatinib group and 10 deaths in the placebo group (log rank test P = 0.64). Thirty-five (29%) patients discontinued the study without reaching the primary endpoint (imatinib, 32%; placebo, 27%; P = 0.51). Serious adverse events (SAEs) were not more common in the imatinib group (imatinib, 18 SAEs in 17 patients; placebo, 19 SAEs in 18 patients). Conclusions: In a randomized, placebo-controlled trial of patients with mild to moderate IPF followed for 96 weeks, imatinib did not affect survival or lung function. Clinical trial registered with www.clinicaltrials.gov (NCT00131274).