BACKGROUND: Nasal high flow (NHF) is an established treatment option in acute respiratory failure and has been shown to increase the elimination of carbon dioxide (CO) in hypercapnic COPD patients. The aim of the study was to investigate the impact on gas exchange, respiratory pattern and sleep quality in severe COPD patients with mild hypercapnic respiratory failure. METHODS: Hypercapnic COPD patients (n=42) underwent a wakefulness ventilation study with calibrated inductance plethysmography followed by two polysomnography (PSG) studies with NHF at 20 L·min and 35 L·min. In a crossover design immediately after hospital discharge, patients were randomised to a 4-week period of nocturnal NHF long-term oxygen therapy (LTOT). The primary outcome was transcutaneous carbon dioxide ( ) measured during PSG after each period. RESULTS: NHF reduced mean overnight by 3.4±6.5 mmHg (p=0.010), attenuating the increase of CO during sleep, with no effect observed during wakefulness when minute ventilation (') and respiratory rate (RR) were decreased. The mean sleep fragmentation index (26.6±11.2) and sleep efficiency (72.8±16.4%) during NHF were not significantly different from those during LTOT (n=24). An increase in NHF did not change ' during wakefulness and did not produce significant effects on ventilation, gas exchange or sleep parameters during the night. CONCLUSION: Nocturnal NHF attenuated an increase of during sleep in hypercapnic COPD patients without a relevant effect on sleep quality compared with LTOT. During wakefulness, was unaffected, but ' and RR were reduced, indicating a different physiological response during wakefulness compared with sleep.