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The efficacy of noninvasive mechanical ventilation (NIMV) in improving breathing pattern and arterial blood gases (ABG) in hypercapnic patients has been well documented; however, little attention has been given to the choice of the interface and the ventilatory mode. We evaluated the effects of three types of masks and two modes of ventilation on patients’ ABG, breathing pattern, and tolerance to ventilation.Prospective randomized study.Two respiratory weaning centers.A total of 26 stable hypercapnic patients (pH, 7.38 ± 0.04; Paco2, 59.2. ± 10.9 torr) had not received NIMV and were affected by restrictive thoracic disease or obstructive pulmonary disease.Three 30-min runs of NIMV, delivered using volume-assisted (n = 13) or pressure-assisted modes of partial mechanical support (n = 13), were performed in random order with a full-face mask, a nasal mask, and nasal plugs.ABG, breathing pattern, and patients’ tolerance to ventilation.Compared with spontaneous breathing, the application of NIMV significantly improved ABG and minute ventilation, irrespective of the ventilatory mode, the underlying pathology or the type of mask. Overall, a nasal mask was better tolerated than the other two interfaces (p < .005 vs. nasal plugs and full-face mask). Paco2 was significantly lower (p < .01) with a full-face mask or nasal plugs than with a nasal mask (49.5 ± 9.4 torr, 49.7 ± 8 torr, and 52.4 ± 11 torr, respectively). Minute ventilation was significantly higher with a full-face mask than with a nasal mask because of an increase in tidal volume. No differences were observed in tolerance to ventilation, ABG, or breathing pattern, using assist control or pressure-assisted modes.In this physiologic study, we have shown that in patients with hypercapnic respiratory failure, irrespective of the underlying pathology, the type of interface affects the NIMV outcome more than the ventilatory mode.