Background: Associations between androgen deprivation therapy (ADT) and increased cardiovascular (CV) risk in prostate cancer (PCa) patients have been reported; however, how many of these major adverse CV events (MACE) are caused by ADT itself has been debated. One risk factor for increased CV risk is a prior history of CV events; an analysis found that each new CV event increased the probability of a future event. This study aims to evaluate the incidence of MACE after ADT initiation for patients with and without a prior medical history of MACE. Methods: Analyses of US electronic medical records (2010 to 2020) of PCa patients (n=45,059) receiving LHRH agonist and antagonist injections were conducted to evaluate MACE incidence after ADT initiation in patients with and without MACE history. Exclusion criteria included lack of ADT initiation date or myocardial infarction (MI)/stroke within 6 months prior to ADT initiation. MACE was defined as MI, stroke, and death from any cause. Kaplan-Meier event-free survival curves were constructed, and Cox regression was used to compare the MACE hazard rates between patients with and without a personal history of MACE. Multivariate Cox regression adjusted for agonists vs antagonist, increasing age per year, BMI (<18.5 vs ≥18.5 kg/m2), race (White vs Black), family MACE history, ethnicity (Hispanic vs non-Hispanic), urology vs oncology setting, history of hypertension, and history of hypercholesterolemia. Results: Overall, MACE incidence was 3.9% and 19.6% for the cohort at one year and four years after ADT initiation, respectively. MACE risk following ADT initiation was higher for patients with history of prior MACE (unadjusted: (HR=2.76, 95% CI [2.49, 3.06], p<0.001); adjusted: HR=2.29, 95% CI [1.93, 2.71], p<0.001). When MACE was divided into component events, the risks of myocardial infarction and stroke were higher for patients with a prior MACE history compared to those without (8 vs. 1% and 8 vs. 2%, respectively), and the risk of any-cause death was similar (13 vs. 14%). Conclusions: MACE incidence in PCa patients in the first year of ADT was consistent with previous publications.(3). When MACE risk was analyzed in detail, ADT patients with a personal history of stroke or myocardial infarction (MI) had a 4- and 8-fold greater risk of a subsequent stroke and MI, respectively, compared to those without a history of stroke or MI. Given the large sample size (~45,000 PCa patients) of this data set over the recent past decade, these results likely reasonably reflect the real world. Urologists and oncologists should work with cardiologists, cardio-oncologists, and primary care practitioners to ensure the highest quality CV care is delivered.