A previous trial of bosentan in idiopathic pulmonary fibrosis (IPF) showed a trend to delayed IPF worsening or death. Also, improvements in some measures of dyspnea and health-related quality of life were observed. To demonstrate that bosentan delays IPF worsening or death. Prospective, randomized (2:1), double-blind, placebo-controlled, event-driven, parallel-group, morbidity-mortality trial of bosentan in adults with IPF of less than 3 years' duration, confirmed by surgical lung biopsy, and without extensive honeycombing on high-resolution computed tomography. The primary endpoint was time to IPF worsening (a confirmed decrease from baseline in FVC ≥ 10% and diffusing capacity of the lung for carbon monoxide ≥ 15%, or acute exacerbation of IPF) or death up to End of Study. Effects of bosentan on health-related quality of life, dyspnea, and the safety and tolerability of bosentan were investigated. Six hundred sixteen patients were randomized to bosentan (n=407) or placebo (=209). No significant difference between treatment groups was observed in the primary endpoint analysis (hazard ratio, 0.85; 95% confidence interval, 0.66-1.10; P=0.2110). No treatment effects were observed on health-related quality of life or dyspnea. Some effects of bosentan treatment were observed in changes from baseline to 1 year in FVC and diffusing capacity of the lung for carbon monoxide. The safety profile for bosentan was similar to that observed in other trials. The primary objective in the Bosentan Use in Interstitial Lung Disease-3 trial was not met. Bosentan was well tolerated. Clinical trial registered with www.clinicaltrials.gov (NCT 00391443).