Background: The dual orexin receptor antagonist daridorexant did not impact nighttime respiratory function as assessed by the apnea/hypopnea index (AHI) and nocturnal oxygen saturation (SpO2) and improved sleep in patients with mild to moderate obstructive sleep apnea (OSA). These analyses were supplemented with further evaluations of various indices of OSA severity and sleep variables. Methods: In this randomized, double-blind, placebo-controlled, two-period, crossover study, 50 mg daridorexant or placebo was administered every evening for 5 days to 28 patients with mild to moderate OSA. Treatment differences (daridorexant – placebo) were explored for indices of OSA severity including the number and duration of apneas and hypopneas, mean and lowest nocturnal SpO2, sleep duration during each hour of polysomnography recording, and the number and mean and longest duration of awakenings. Results: After repeated-dose daridorexant, more respiratory events were observed compared to placebo, ie., treatment difference of 16.4 events (90% confidence interval: −0.4, 33.2) which is explained by a longer total sleep time. However, no treatment difference was detected for the longest duration of apneas and hypopneas (1.5 s [–8.3, 11.2] and 8.2 s [–6.6, 23.0], respectively), and lowest SpO2 (0.9% [–0.3, 2.1]). The number of awakenings was similar between daridorexant and placebo while daridorexant shortened the longest duration by 16.2 min (8.5, 23.8). Overall, results were similar after single and repeated dosing for both respiratory and sleep aspects. Conclusion: These results suggest safe use of daridorexant in patients with mild to moderate OSA. Clinical trial registration: ClinicalTrials.gov NCT03765294. A study to investigate the effects of ACT-541468 on nighttime respiratory function in patients with mild to moderate obstructive sleep apnea. https://clinicaltrials.gov/ct2/show/NCT03765294.