Background: Robustassessment of comorbid conditions is essential to clinical care and the risk-stratification of patients for adverse events and death. Prescription medications may be a simple and readily available tool to estimate patient risk independent of established comorbidity indices, such as the Charlson Comorbidity Index (CCI). Clinicians have access to medication lists, facilitating assessment of comorbidities. We sought to examine the relationship between prescription medications and long-term outcomes in veterans treated for metastatic hormone-sensitive prostate cancer (mHSPC). Methods: We conducted a nationwide retrospective observational study of United States Veterans diagnosed with mHSPC in the Veterans Health Administration from 2010-2021. We determined the number of unique drugs and their respective Anatomic Therapeutic Chemical (ATC) Level One classes prescribed in the year prior to the 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 covariates including age, CCI, body mass index, prostate specific antigen, and race. Results: Among 8,434 Veterans, a median (IQR) of 9 (5-14) unique medications and 5 (3-7) unique ATC medication classes were filled in the year prior to treatment. The mean age was 74.2 (SD 10.1) years, and 2,126 Veterans were black (25.2%). The median CCI was 3 (2.75-6). Increasing age was associated with increased CCI across age strata with mean CCI of 3.16 in age <60, 3.76 in 60-70, 4.43 in 70-80, and 5.25 in 80+ (p<0.001). Increasing age was associated with an increased number of unique medicines with mean 8.59 in age <60, 9.53 in 60-70, 10.1 in 70-80, and 10.4 in 80+ (p<0.001). There was no significant difference in the number of medications prescribed based on race. Veterans with 1-4 medicines had the longest average survival at 38.2 months compared to 5-9 medicines (33.1 months), 10-14 medicines (27.1 months), and 15+ medicines (22.0 months) (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 mortality with adjusted HR (95% CI) of 1.03 (1.02-1.03) and 1.05 (1.04-1.07), respectively. Veterans treated with 5-9, 10-14, and 15+ medicines had an increased risk of death compared to Veterans on 1-4 medicines [aHR 1.11 (1.03-1.19); 1.29 (1.19-1.39); and 1.51 (1.39-1.65) respectively]. Conclusions: The number of prescription medications and drug classes are independently associated with OS in patients diagnosed with mHSPC, 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.