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Daridorexant is a dual orexin receptor antagonist approved for the treatment of adult patients with chronic insomnia disorder. In a previous phase 1 trial, daridorexant was shown to have no negative effect on sleep-disordered breathing in patients with mild to moderate obstructive sleep apnea (OSA).This randomized, double-blind, placebo-controlled, crossover phase 1 trial, evaluated the safety of repeated dosing (5 nights) of 50 mg daridorexant in sixteen patients with severe OSA without insomnia.. Other respiratory variables, including indices of disease severity, were explored using treatment difference (daridorexant– placebo) and its two-sided 90% CI. The effect of daridorexant on sleep was explored based on total sleep time (TST), rapid eye movement (REM), and non-REM sleep.Baseline AHI and mean nocturnal SpO2 were 51.2 events/h (standard deviation [SD]: 17.0) and 92.1% (SD: 1.7), respectively. No clinically meaningful effect of 50 mg daridorexant on AHI and mean nocturnal SpO2 were detected. Treatment differences were -3.74 events/h (upper 95% CI: ≤ 4.23 events/h) and -0.12 % (lower 95% CI: ≥ -0.62 %), respectively. AHI and mean SpO2 during non-REM were comparable after daridorexant and placebo administration. AHI showed improvement during REM sleep after daridorexant administration as treatment difference (daridorexant–placebo) was -8.2 events/h (90% CI: -13.7, -2.7). No treatment difference was observed for the evaluated indices of disease severity, e.g., the total number of apneas and hypopneas and their longest duration, lowest SpO2 during respiratory events, or %TST with SpO2 < 90%. Compared with placebo, daridorexant increased TST by 32.5 min mainly via the increased duration of REM sleep. Three out of six adverse events were under daridorexant (all mild), none were related to respiratory function.Daridorexant does not impair sleep-disordered breathing and may improve sleep in patients with severe OSA. Daridorexant does not impair sleep-disordered breathing, independent of OSA severity.Funding Idorsia Pharmaceuticals Ltd