Lemborexant is a dual orexin receptor antagonist indicated for the treatment of adult and elderly individuals with insomnia. Some current pharmacologic treatments for insomnia cause respiratory depression, a serious safety concern, particularly for individuals with obstructive sleep apnea (OSA). This phase 1, randomized, double-blind, placebo-controlled, two-period crossover study examined respiratory safety parameters in individuals with mild OSA following treatment with lemborexant. Participants (n = 39) were randomized to one of two treatment sequences, including placebo and lemborexant 10 mg. Each treatment period lasted 8 days and was separated by a washout of at least 14 days. Following single or multiple doses, there were no significant differences in mean apnea-hypopnea index for lemborexant 10 mg versus placebo (least squares mean [LSM] difference [95% confidence interval {CI}]: day 1, -0.03 [-2.22, 2.17]; day 8, -0.06 [-1.95, 1.83]) or peripheral capillary oxygen saturation during sleep (LSM difference [95% CI]: day 1, 0.07 [-0.31, 0.46]; day 8, 0.25 [-0.11, 0.61]). There were no significant differences versus placebo for the percentage of total sleep time during which peripheral capillary oxygen saturation was <80% (LSM difference [95% CI]: day 1, 0.002 [-0.019, 0.023]; day 8, 0.006 [-0.015, 0.026]), <85% (LSM difference [95% CI]: day 1, 0.067 [-0.124, 0.258]; day 8, 0.056 [-0.117, 0.228]) or <90% (LSM difference [95% CI]: day 1, 0.312 [-0.558, 1.181]; day 8, 0.088 [-0.431, 0.607]). The incidence of treatment-emergent adverse events was low and similar for lemborexant and placebo. Lemborexant demonstrated respiratory safety in this study population and was well tolerated.© 2020 The Authors. Journal of Sleep Research published by John Wiley & Sons Ltd on behalf of European Sleep Research Society.