Noninvasive ventilation (NIV) settings determined during wakefulness may produce patient–ventilator asynchrony (PVA) during sleep, causing sleep disruption and limiting tolerance. This study investigated whether NIV titrated with polysomnography (PSG) is associated with less PVA and sleep disruption than therapy titrated during daytime alone.Treatment-naive individuals referred for NIV were randomised to control (daytime titration followed by sham polysomnographic titration) or PSG (daytime titration followed by polysomnographic titration) groups. Primary outcomes were PVA and arousal indices on PSG at 10 weeks. Secondary outcomes included adherence, gas exchange, symptoms and health-related quality of life (HRQoL).In total, 60 participants were randomised. Most (88.3%) had a neuromuscular disorder and respiratory muscle weakness but minor derangements in daytime arterial blood gases. PVA events were less frequent in those undergoing polysomnographic titration (median (interquartile range (IQR)): PSG 25.7 (12–68) events·h−1versus control 41.0 (28–182) events·h−1; p=0.046), but arousals were not significantly different (median (IQR): PSG 11.4 (9–19) arousals·h−1versus control 14.6 (11–19) arousals·h−1; p=0.258). Overall adherence was not different except in those with poor early adherence (<4 h·day−1) who increased their use after polysomnographic titration (mean difference: PSG 95 (95% CI 29–161) min·day−1versus control −23 (95% CI −86–39) min·day−1; p=0.01). Arterial carbon dioxide tension, somnolence and sleep quality improved in both groups. There were no differences in nocturnal gas exchange or overall measures of HRQoL.NIV titrated with PSG is associated with less PVA but not less sleep disruption when compared with therapy titrated during daytime alone.