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Rationale: The interest of non-invasive ventilation (NIV) as an early weaning/extubation technique from mechanical ventilation remains controversial. Objectives: To investigate NIV effectiveness as an early weaning/extubation technique in difficult-to-wean chronic hypercapnic respiratory failure (CHRF) patients. Methods: In 13 ICUs, 208 CHRF patients intubated for acute respiratory failure (ARF) who failed a first spontaneous breathing trial were randomly assigned to three groups: conventional invasive weaning group (n=69), extubation followed by standard oxygen-therapy (n=70) or NIV (n=69). NIV was permitted as rescue therapy for both non-NIV groups if post-extubation ARF occurred. Primary endpoint was reintubation within seven days following extubation. Secondary endpoints were: occurrence of post-extubation ARF or death within, use of rescue post-extubation NIV, weaning time, and patients outcome. Measurements and main results: Reintubation rates were 30%, 37% and 32% for invasive weaning, oxygen-therapy and NIV group, respectively (p=0.654). Weaning failure rates, including post-extubation ARF, were 54%, 71% and 33%, respectively (p<0.001). Rescue NIV success rates for invasive and oxygen-therapy groups were 45% and 58%, respectively (p=0.386). By design, intubation duration was 1.5 day longer for the invasive group than in the two others. Apart from a longer weaning time in NIV than in invasive group (2.5 vs. 1.5 days; p=0.033), no significant outcome difference was observed between groups. Conclusions: No difference was found in the reintubation rate between the three weaning strategies. NIV decreases the intubation duration and may improve the weaning results in difficult-to-wean CHRF patients by reducing the risk of post-extubation ARF. The benefit of rescue NIV in these patients deserves confirmation