118 Background: The majority of new cancer diagnoses occur in adults greater than 65 years of age. Polypharmacy is a common and potentially devastating problem amongst older adults; however, its prevalence and impact in older adults with gastrointestinal (GI) malignancy is poorly understood. Our objective was to examine the prevalence of polypharmacy and its association with functional status impairments, frailty, and health-related quality of life (HRQoL) in older adults with GI malignancy. Methods: The Cancer and Aging Resilience Evaluation (CARE) registry at the University of Alabama at Birmingham (UAB) is an ongoing prospective cohort study that uses a brief geriatric assessment (CARE survey) in older adults with cancer. We evaluated older adults diagnosed with GI malignancy prior to starting cancer therapy. Our primary outcomes of interest were functional status impairments, including dependence in activities of daily living (ADL) and instrumental activities of daily living (IADL), frailty (as defined by a frailty index derived using the principles of deficit accumulation), and HRQoL (assessed via PROMIS 10 global that includes physical and mental scores). Patients were dichotomized into those taking ≥9 vs. < 9 medications. Multivariable analyses examined associations between polypharmacy and the above-listed outcomes, adjusted for age, sex, race, cancer type, cancer stage, and comorbidities. Results: Overall, 357 patients met eligibility criteria; mean age: 70.1 years; primary diagnoses: colorectal (33.6%), pancreatic (24.6%), hepatobiliary (16.2%), gastroesophageal (10.9%), other (14.6%). Patients reported taking a mean of 6.2 medications: 27.7% with 0-3 medications, 48.2% with 4-8 medications, and 24.1% with ≥ 9 medications. Patients taking ≥ 9 medications were more likely to report limitations in ADL (adjusted odds ratio [aOR] 3.29, 95% CI 1.72-6.29) and IADL (aOR 2.86, 95% CI 1.59-5.14). Polypharmacy was also associated with frailty (aOR 3.06, 95% CI 1.73-5.41) and lower physical (aOR 2.82, 95% CI 1.70-4.69) and mental (aOR 1.73, 95% CI 1.03-2.91) HRQoL. Conclusions: Independent of comorbid conditions, polypharmacy was associated with functional status limitations, frailty, and reduced HRQoL in older adults with GI malignancy. Further study of specific medications and interactions is warranted in order to reduce the negative consequences of polypharmacy in this growing and vulnerable population.