Abstract Background: Assessment of comorbid diseases is essential to clinical research and may risk-stratify patients for adverse events and death. Total number of prescription medications and drug classes could be an easy-to-use tool for estimating patient risk independent of established methods such as the Charlson Comorbidity Index (CCI) that is created from administrative data. Additionally, clinicians have access to prescription medication lists, facilitating assessment of comorbidities in clinical settings. Methods: Retrospective observational study of US Veterans treated for metastatic castrate resistant prostate cancer in the Veterans Health Administration who received treatment with abiraterone or enzalutamide between May 2011-June 2, 2017. We determined number of unique drugs and anatomic therapeutic chemical (ATC) drug classes prescribed in the year prior up to 14 days before initiation of treatment. Multivariable logistic regression and Cox proportional hazard modeling was used to assess the association between number of drugs with all-cause 90-day mortality and overall survival (OS) while accounting for important covariates including age, CCI, body-mass index, prostate specific antigen, race, prior docetaxel, hemoglobin, albumin, bilirubin, and creatinine. Results: Among 11,021 Veterans, a median (IQR) of 11 (6,18) unique medications and 10 (5,15) unique ATC medication classes were filled in the year prior to treatment. The median age was 75 years with median CCI of 3 and 2,550 were black (23.1%). Increasing age was associated with increased CCI across age strata with mean CCI of 3.7 in age <70, 4.2 in age 70-79, and 4.3 in age 80+ (p<0.001). Increased age was associated with decreased number of unique medicines with mean 14.7 in age <70, 12.7 in age 70-79, and 11.2 in age 80+ (p<0.001). Black race was associated with increased mean number of medications compared to white race (15.5 vs. 12.0, p<0.001). After adjusting for relevant patient, tumor, and treatment factors, the number of medications and drug classes were each independently associated with increased 90-day mortality with adjusted OR (95% CI) of 1.021 (1.011,1.030) and 1.024 (1.012,1.036) respectively. Both number of medications and number of classes were also associated with decreased OS with adjusted Hazard Ratio of 1.015 (1.013,1.018) and 1.018 (1.014,1.021) respectively. Within subgroups of patients with comparable CCI, increased number of medications was associated with increased risk of death. Conclusion: The number of prescription medications and drug classes are independently associated with short- and long-term outcomes in patients undergoing treatment for metastatic castrate resistant prostate cancer, even after accounting for important covariates including age and CCI. Assessment of patient medications may provide a simple, yet reliable tool to assess comorbidities, risk of adverse events, and death. Citation Format: Martin W. Schoen, Carley Pickett, Daniel B. Eaton, Brendan T. Heiden, Su-Hsin Chang, Yan Yan, Melanie P. Subramanian, Varun Puri. Number of prescription drugs and overall survival in metastatic castrate resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6741.