BACKGROUND: There were three phase 3 trials, two of which showed that pirfenidone (an oral antifibrotic drug) reduced disease progression, as measured by a reduction in forceful lung volume (FVC) or spirometry, in patients with idiopathic pulmonary fibrosis; in the third trial, this endpoint outcome was not found to be met. We sought to confirm the beneficial effect of pirfenidone in reducing disease progression in such patients. METHODS: In this phase 3 study, we randomly assigned 555 patients with idiopathic pulmonary fibrosis to receive either oral pirfenidone (2403 mg daily) or placebo for 52 weeks. The primary endpoint was change in exertional spirometry or death at 52 weeks. Secondary endpoints were 6-min walking distance, progression-free survival, dyspnea, and death from any cause or idiopathic pulmonary fibrosis. RESULTS: In the pirfenidone group, there was a 47.9% relative decrease in the percentage of patients with an absolute reduction in predicted exertional spirometry of 10 percentage points or more or death compared with the placebo group; there was also a 132.5% relative increase in the percentage of patients with no reduction in exertional spirometry (P<0.001). Pirfenidone alleviated the reduction in 6 min walking distance (P=0.04) and improved progression-free survival (P<0.001). There were no significant between-group differences in dyspnea scores (P=0.16), mortality from any cause (P=0.10), or mortality due to idiopathic pulmonary fibrosis (P=0.23). However, in a pre-designed pooled analysis of the combined results from two prior phase 3 trials, between-group differences in death from any cause (P=0.01) and death from idiopathic pulmonary fibrosis (P=0.006) were significant and favored pirfenidone. CONCLUSION: Pirfenidone reduced disease progression in patients with idiopathic pulmonary fibrosis compared with placebo, as reflected in lung function, exercise tolerance, and progression-free survival. Treatment was associated with acceptable side effects and fewer deaths.