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Ali A El-Solh,1– 3 Yolanda Lawson,1 Gregory E Wilding4 1Research Department, VA Western New York Healthcare System, Buffalo, NY, USA; 2Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine; Jacobs School of Medicine, Buffalo, NY, USA; 3Department of Epidemiology and Environmental Health, School of Public Health and Health Professions; University at Buffalo, Buffalo, NY, USA; 4Department of Biostatistics, School of Public Health and Health Professions; University at Buffalo, Buffalo, NY, USACorrespondence: Ali A El-Solh, Research Department, VA Western New York Healthcare System, 3495 Bailey Avenue, Buffalo, NY, 14215, USA, Tel +1 (716) 862-7392, Fax +1 (716) 862-6526, Email solh@buffalo.eduPurpose: Hypnotics are commonly prescribed in patients with COPD to manage insomnia. Given the considerable risks associated with these drugs, the aim of the study was to evaluate the risk of all-cause mortality associated with hypnotics in a cohort of veterans with COPD presenting with insomnia.Methods: We conducted a retrospective cohort study that used Veterans Health Administration Corporate Data Warehouse with data supplemented by linkage to Medicare, Medicaid, and National Death Index data from 2010 through 2019. The primary outcome was all-cause mortality. Analyses were conducted using propensity score 1:1 matching to balance baseline characteristics.Results: Of the 5759 veterans with COPD (mean [SD] age, 71.7 [11.2]; 92% men), 3585 newly initiated hypnotic agents during the study period. During a mean follow-up of 7.4 (SD, 2.7) years, a total of 2301 deaths occurred, with 65.2 and 48.7 total deaths per 1000 person-years among hypnotic users and nonusers, respectively. After propensity matching, hypnotic use was associated with a 22% increased risk of mortality compared with hypnotic nonusers (hazard ratio [HR] 1.22; 95% confidence interval [CI],1.11– 1.35). The benzodiazepine receptor agonists (BZRAs) group experienced a higher incidence rate of all-cause mortality compared to hypnotic nonusers (Incidence rate ratio [IRR] 1.27; 95% CI, 1.14– 1.43). Conversely, the mortality rate of non-BZRA hypnotics decreased after the first 2 years and was not significantly different for hypnotic nonusers (IRR 1.04; 95% CI, 0.82– 1.11).Conclusion: Among patients with COPD and insomnia, treatment with hypnotics was associated with a higher risk of all-cause mortality. The association was observed in patients prescribed BZRAs. The risk of mortality for non-BZRAs moderated after the first 2 years, indicating a class effect.Keywords: insomnia, chronic obstructive pulmonary disease, mortality, benzodiazepine receptor agonists