Abstract Purpose: The purpose of this study is to investigate associations of discontinuing vs continuing long-term opioid therapy (LTOT) with pain, physical function, and depressive symptoms among older cancer survivors who resided in nursing homes. Pain is prevalent and use of LTOT is common among patients with cancer, including those living in nursing homes. The Centers for Disease Control and Prevention (CDC) Guideline for Prescribing Opioids for Chronic Pain—United States recommends tapering or discontinuing LTOT for patients with chronic pain when risks outweigh the benefits of LTOT. Despite the guideline explicitly stating that its recommendation does not apply to patients with cancer, doctors including oncologists have been prescribing fewer opioid medications for older patients, raising a question regarding the benefit and risk of discontinuing LTOT for cancer survivors who depend on opioids for pain relief. Study Design: We conducted a cohort study using a 100% Medicare nursing home sample linked to the Minimum Data Set (MDS) from 2010 to 2021. Participants included older (≥65 years of age) long-term (≥2 years) residents with a diagnosis of cancer who received LTOT for ≥90 days in a 12-month nursing home stay. Residents entered the cohort on the 90th day of the latest LTOT episode. Residents who received palliative or hospice care were excluded. The key exposure was discontinuation of LTOT, defined as no opioid refills for ≥90 consecutive days in 1 year after cohort entry. The primary outcomes were pain (measured using a numerical rating scale or categorical verbal descriptor scale), physical function (9-item activities of daily living scale), and depression (Patient Health Questionnaire-9) from baseline to quarterly assessments during 1-year follow-up after the discontinuation of LTOT. Results: In total, 53,141 cancer survivors who received LTOT were identified (mean [SD] age, 82.9 [8.7] years; 39,522 [74.4%] female; 46678 [87.8] Whites), consisting of 62,387 patient observations during the 10-year study period. Of 62,387 patient observations, 51,357 residents (82.3%) continued LTOT, and 11,030 (17.6%) discontinued LTOT. Residents who discontinued (vs continued) LTOT had lower odds of worsening pain (adjusted odds ratio [AOR], 0.64, 95% CI, 0.59-0.59, P < .001) and depressive symptoms (AOR, 0.92 [95% CI, 0.85-0.99]; P = .033), with no difference in physical function (AOR, 0.96 [95% CI, 0.89-1.03]; P = .226) during the 1-year follow-up. Conclusion: Among older nursing home residents with cancer, discontinuing vs continuing LTOT was associated with lower odds of worsening pain and depressive symptoms. Funding source: NIH/NIA R01AG073442. Citation Format: Yu-Jung Jenny Wei, Almut G. Winterstein, Siegfried Schmidt, Roger B. Fillingim, Michael Daniels, Steven T. DeKosky, Ben Kinder, Ting-Yuan David Cheng. Clinical outcomes of discontinuing long-term opioid therapy among older cancer survivors in nursing homes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2249.