Background: Cardiovascular risk factor modification is crucial for cancer patients, particularly for those receiving hormonal therapy due to the increased risk of cardiovascular disease (CVD). However, the evaluation of cardiovascular risk in prostate cancer patients undergoing novel hormonal therapy (NHT) remains not well understood. This study aimed to assess the incidence of cardiovascular events in patients with prostate cancer initiating NHT and compare the risk with non-cancer matched controls. Methods: This study is a retrospective cohort analysis that examined electronic medical records from a global federated health research network, TriNetX. The study included male patients with prostate cancer who were 18 years or older and had initiated treatment with abiraterone, enzalutamide, apalutamide, or darolutamide between January 1, 2015, and December 31, 2020. The cohort was stratified based on diabetes mellitus (DM) and prior CVD status. We evaluated the incidence of myocardial infarction (MI) within 1 and 3 years after NHT initiation. MI risk was compared between each strata of cancer patients and propensity score matched non-cancer patients with cox proportional hazards models, with a significance threshold of p<0.05. Results: There were 11,536 patients with prostate cancer receiving NHT, having a mean age of 70.4 years and predominately White (70%). Of this cohort, 22% had DM, 23% had CVD, and 62% had neither condition. One- and 3-year incidence of MI was 5% and 7% amongst all patients; those with DM, CVD, or both had higher incidences of MI at 3 years, with the rates of 13%, 18%, 22% respectively. Adjusted analyses showed that prostate cancer patients initiating NHT had significantly higher hazards of MI compared to matched non-cancer controls (HR: 1.57 [95% CI: 1.32-1.86] for DM, 1.31 [95% CI: 1.14-1.50] for CVD, and 1.29 [95% CI: 1.05-1.57] for both DM and CVD). Conclusions: The incidence of MI is relatively low in prostate cancer patients starting NHT without DM or CVD comorbidities. However, those patients with pre-existing DM and/or CVD are at significantly higher risk of MI, even more than age matched controls without cancer with those co-morbidities. This highlights the need for comprehensive cardiovascular risk stratification and management in high-risk patients with prostate cancer.