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Objective: Evidence that PS may facilitate weaning from mechanical ventilation (MV), although not confirmed by randomized trials, prompted us to investigate whether patients could be weaned with PS after failing a T-tube trial., Design and Setting: This was a prospective, non-randomized study in two French intensive care units., Patients and Participants: One hundred eighteen patients were enrolled and underwent a T-tube trial, after which 87 were extubated. Thirty-one underwent a further trial with PS, after which 21 were extubated., Interventions: All patients under MV >24 h meeting the criteria for a weaning test underwent a 30-min T-tube trial. If this was successful, they were immediately extubated. Otherwise, a 30-min trial with +7 cm H2O PS was initiated with an individualized pressurization slope and trigger adjustment. If all weaning criteria were met, the patients were extubated; otherwise, MV was reinstated., Measurements and Results: The extubation failure rate at 48 h did not differ significantly between the groups: 11/87 (13%) versus 4/21 (19%), P=0.39. The groups were comparable with regard to endotracheal tube diameter, MV duration, the use of non-invasive ventilation (NIV) after extubation, initial severity score, age and underlying pathology, except for COPD. A significantly higher percentage of patients with COPD was extubated after the trial with PS (8/21-38%) than after a single T-tube trial (11/87-13%) (P=0.003)., Conclusions: Of the patients, 21/118 (18%) could be extubated after a trial with PS, despite having failed a T-tube trial. The reintubation rate was not increased. This protocol may particularly benefit patients who are most difficult to wean, notably those with COPD.