Background: COMISA (comorbid insomnia and obstructive sleep apnea) is associated with daytime functioning and cognitive impairments. This post hoc analysis assessed the impact of lemborexant (LEM), a dual-orexin-receptor-antagonist approved to treat insomnia in adults, on morning sleepiness/alertness in participants with COMISA. Methods: Of the overall population (n=1006), 410 (40.8%) adults (≥55 years) with comorbid insomnia disorder and mild obstructive sleep apnea (apnea-hypopnea-index, 5–≤15 events/h) from Study E2006-G000-304 (NCT02783729), a 1-month, randomized, placebo- and active-controlled study, were analyzed. Participants received placebo (PBO), LEM 5mg (LEM5), LEM 10mg (LEM10), or zolpidem tartrate 6.25mg (not reported). A daily sleep diary assessed morning sleepiness/alertness (1, extremely sleepy to 9, extremely alert). Participants (%) shifting from baseline mild/moderate sleepiness (≤3) towards greater alertness (4, 5, or >5) during the first/last 7 mornings of the study were analyzed. Results: At baseline, 17/75 (22.7%), 36/112 (32.1%), and 28/104 (26.9%) participants with COMISA receiving PBO, LEM5, or LEM10, respectively, reported mild/moderate sleepiness. Across the first/last 7 mornings, more participants shifted from mild/moderate sleepiness towards alertness with LEM5 (66.7%, 82.9%) and LEM10 (64.3%, 75.0%) versus PBO (47.1%, 64.7%), respectively. Conclusions: A greater percentage of participants with COMISA experienced improvements in morning sleepiness across the treatment period with LEM versus PBO.