12036 Background: Older adults share a growing burden of cancer morbidity and mortality. The presence of comorbid medical conditions and polypharmacy may present significant challenges to cancer management for older adults. Although geriatric assessment (GA) is recommended to personalize treatment for older adults with cancer, it remains underutilized in routine oncology practice, and how best to measure comorbidity and polypharmacy remain unknown. The Comorbidity Polypharmacy Score (CPS), which is the sum of the number of comorbid medical conditions and medications for a patient, has been validated in other medical fields. Here we review the association of CPS with key outcomes among older adults with gastrointestinal (GI) malignancy. Methods: The Cancer and Aging Resilience Evaluation (CARE) tool is a brief, patient-completed GA developed for older adults with cancer at the University of Alabama at Birmingham (UAB). For patients enrolled in the CARE registry, diagnosed with a new GI malignancy between September 2017 and April 2021, we calculated a CPS based upon the number of patient-reported medical comorbid conditions and daily medications. Patients were separated into two groups, those with CPS ≥ 15, or high-risk, and those with CPS < 15. Multivariable analyses were adjusted for age, sex, race, cancer type, and cancer stage, and were performed to examine the potential association between high-risk CPS and falls, functional limitations, frailty, and mortality. Results: 548 patients were included in this study with a mean age of 69.7 years; 44.9% female and 23.9% Black. Common GI malignancies included colorectal (30.8%), pancreatic (25.5%), hepatobiliary (17.7%), and gastroesophageal (10.8%). Patients with CPS ≥ 15 were more likely to report falls (adjusted odds ratio [aOR] 3.39, 95% CI 1.91-6.02), dependence in activities of daily living (ADL) (aOR 3.07, 95% CI 1.67-5.66) and instrumental ADL (aOR 3.81, 95% CI 2.02-7.20), and have frailty (aOR 5.17, 95% CI 2.84-9.39). There was not a statistically significant association with either six-month or twelve-month survival. Conclusions: CPS was associated with falls, functional limitations, and frailty, but not survival, among older adults with GI malignancies. This association highlights the potential role of CPS as an efficient screening tool for older adults with cancer who would benefit from more comprehensive comorbidity and medication review.