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To assess the effect of a helium-oxygen mixture on intubation rate and clinical outcomes during noninvasive ventilation in acute exacerbation of chronic obstructive pulmonary disease.Multicenter, prospective, randomized, controlled trial.Seven intensive care units.A total of 204 patients with known or suspected chronic obstructive pulmonary disease and acute dyspnea, Paco2> 45 mm Hg and two among the following factors: pH <7.35, Paco2 <50 mm Hg, respiratory rate >25/min.Noninvasive ventilation randomly applied with or without helium (inspired oxygen fraction 0.35) via a face mask.Duration and complications of NIV and mechanical ventilation, endotracheal intubation, discharge from intensive care unit and hospital, mortality at day 28, adverse and serious adverse events were recorded. Follow-up lasted until 28 days since enrollment. Intubation rate did not significantly differ between groups (24.5% vs. 30.4% with or without helium, p = .35). No difference was observed in terms of improvement of arterial blood gases, dyspnea, and respiratory rate between groups. Duration of noninvasive ventilation, length of stay, 28-day mortality, complications and adverse events were similar, although serious adverse events tended to be lower with helium (10.8% vs. 19.6%, p = .08).Despite small trends favoring helium, this study did not show a statistical superiority of using helium during NIV to decrease the intubation rate in acute exacerbation of chronic obstructive pulmonary disease.