Supplemental oxygen is commonly prescribed in patients with idiopathic pulmonary fibrosis (IPF), although its benefits have not been proven. The aims of this study were to investigate the effect of oxygen on oxidative stress, cytokine production, skeletal muscle metabolism and physiological response to exercise in IPF.Eleven participants with IPF received either oxygen, at an FiO2 of 0.50, or compressed air for 1 h at rest and during a cycle endurance test at 85% of peak work rate. Blood samples collected at rest and during exercise were analysed for markers of oxidative stress, skeletal muscle metabolism and cytokines. The protocol was repeated a week later with the alternate intervention.Compared with air, oxygen did not adversely affect biomarker concentrations at rest and significantly improved endurance time (mean difference = 99 ± 81s, P = 0.002), dyspnoea (-1 ± 1 U, P = 0.02), systolic blood pressure (BP; -11 ± 11 mm Hg, P = 0.006), nadir oxyhaemoglobin saturation (SpO2 ; 8 ± 6%, P = 0.001), SpO2 at 2-min (7 ± 6%, P = 0.003) and 5-min isotimes (5 ± 3, P < 0.001) and peak exercise xanthine concentrations (-42 ± 73 µmol/L, P = 0.03). Air significantly increased IL-10 (5 ± 5 pg/mL, P = 0.04) at 2-min isotime. Thiobarbituric acid-reactive substances (TBARs), IL-6, TNF-α, creatine kinase, lactate, heart rate and fatigue did not differ between the two interventions at any time point.In patients with IPF, breathing oxygen at FiO2 of 0.50 at rest seems safe. During exercise, oxygen improves exercise tolerance, alleviates exercise-induced hypoxaemia and reduces dyspnoea. A potential relationship between oxygen administration and improved skeletal muscle metabolism should be explored in future studies.