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Compared with standard medical therapy (SMT), noninvasive ventilation (NIV) does not reduce the need for reintubation in unselected patients who develop respiratory failure after extubation. The goal of this study was to assess whether early application of NIV, immediately after extubation, is effective in preventing postextubation respiratory failure in an at-risk population.Multiple-center, randomized controlled study.Multiple hospitals.Ninety-seven consecutive patients with similar baseline characteristics, requiring >48 hrs of mechanical ventilation and considered at risk of developing postextubation respiratory failure (i.e., patients who had hypercapnia, congestive heart failure, ineffective cough and excessive tracheobronchial secretions, more than one failure of a weaning trial, more than one comorbid condition, and upper airway obstruction).After a successful weaning trial, the patients were randomized to receive NIV for ≥8 hrs a day in the first 48 hrs or SMT. Primary outcome was the need for reintubation according to standardized criteria. Secondary outcomes were intensive care unit and hospital mortality, as well as time spent in the intensive care unit and in hospital.Compared with the SMT group, the NIV group had a lower rate of reintubation (four of 48 vs. 12 of 49; p = .027). The need for reintubation was associated with a higher risk of mortality (p < .01). The use of NIV resulted in a reduction of risk of intensive care unit mortality (−10%, p < .01), mediated by the reduction for the need of reintubation.NIV was more effective than SMT in preventing postextubation respiratory failure in a population considered at risk of developing this complication.