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INTRODUCTION: Psychoactive substance use may be risky for adults with functional impairments. This study investigates cannabis use and prescription opioid and tranquilizer/sedative (mis)use among adults aged ≥50 years reporting functional impairments in the U.S. METHODS: This cross-sectional analysis of adults aged ≥50 years from the 2015–2019 cohorts of the National Survey on Drug Use and Health estimates the prevalence of past-year medical and nonmedical cannabis use, and prescription opioid and tranquilizer/sedative use and misuse, according to the number of functional impairments reported. The adjusted odds of medical and nonmedical use or misuse of each substance in relation to any impairment, number of impairments, and specific impairments were estimated using logistic regression. Analyses were conducted in December 2020. RESULTS: Compared with those reporting no impairments, those reporting any impairment were more likely to report use of cannabis and (mis)use of prescription opioids and tranquilizers/sedatives (all p