Background <p>Androgen deprivation therapy (ADT) is the cornerstone treatment strategy for men diagnosed with high-risk prostate cancer (PC) but may increase risk for major adverse cardiovascular events (MACE). We examined whether men treated with ADT and radiation therapy (ADT + RT) developed MACE at a higher rate than men receiving RT alone. Secondly, we sought to determine if Black men receiving RT + ADT developed MACE at a higher rate than White men.</p> Methods <p>This retrospective cohort study examined time to diagnosis of MACE among Veterans with PC. We used a 1:1 propensity score matching process to determine whether treatment type (ADT + RT vs. RT alone), race (Black vs. White men) or having a previous diagnosis of a cardiometabolic disease (CMD) were associated with differences in the rate at which men develop MACE.</p> Results <p>Veterans with PC were White (68%) and Black (32%). At PC diagnosis, the mean age was 65.9 years. The majority had stage 2 disease (83.0%) classified as intermediate risk (43.1%). Treatment-matched models showed men receiving ADT + RT were less likely to develop MACE when they no pre-existing CMD. Men treated with ADT + RT or RT alone had significantly increased risks of MACE is they had pre-existing CMD. Black men had the same risk of MACE as non-Hispanic Whites.</p> Conclusions <p>Preexisting CMD and multimorbidity are significant risks for MACE among men treated for PC within the VA healthcare system whether treated with ADT + RT or with RT alone, highlighting the importance pretreatment optimization of comorbidities.</p>