Background: High-intensity noninvasive positive pressure ventilation (NPPV) is a novel ventilatory approach to maximally decreasing elevated arterial carbon dioxide tension (PaCO2) toward normocapnia with stepwise up-titration of pressure support. We tested whether high-intensity NPPV is more effective than low-intensity NPPV at decreasing PaCO2, reducing inspiratory effort, alleviating dyspnoea, improving consciousness, and improving NPPV tolerance in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Methods: In this physiological, randomised controlled trial, we assigned 24 AECOPD patients to undergo either high-intensity NPPV (n = 12) or low-intensity NPPV (n = 12). The primary outcome was PaCO(2 )24 h after randomisation. Secondary outcomes included gas exchange other than PaCO2 24 h after randomisation, inspiratory effort, dyspnoea, consciousness, NPPV tolerance, patient-ventilator asynchrony, cardiac function, ventilator-induced lung injury (VILI), and NPPV-related adverse events. Results: Inspiratory positive airway pressure 24 h after randomisation was significantly higher (28.0 [26.0-28.0] vs. 15.5 [15.0-17.5] cmH(2)O; p= 0.000) and NPPV duration within the first 24 h was significantly longer (21.8 +/- 2.1 vs. 15.3 +/- 4.7 h; p =0.001) in the high-intensity NPPV group. PaCO(2 )24 h after randomisation decreased to 54.0 +/- 11.6 mmHg in the high-intensity NPPV group but only decreased to 67.4 +/- 10.6 mmHg in the low-intensity NPPV group (p= 0.008). Inspiratory oesophageal pressure swing, oesophageal pressure-time product (PTPes)/breath, PTPes/min, and PTPes/L were significantly lower in the high-intensity group. Accessory muscle use and dyspnoea score 24 h after randomisation were also significantly lower in that group. No significant between-groups differences were observed in consciousness, NPPV tolerance, patient-ventilator asynchrony, cardiac function, VILI, or NPPV-related adverse events. Conclusions: High-intensity NPPV is more effective than low-intensity NPPV at decreasing elevated PaCO2, reducing inspiratory effort, and alleviating dyspnoea in AECOPD patients.