Background <p>Chemotherapy-naïve patients with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone (ABI) have a higher cardiovascular (CV) event-related hospitalization risk than those treated with enzalutamide (ENZA). This study aimed to assess CV event risk in chemotherapy-naïve patients with mCRPC treated with ENZA or ABI and to provide outcome data based on CV disease (CVD) history using the US Medicare database.</p> Methods <p>Chemotherapy-naïve patients with mCRPC (≥ 65&#xa0;years) who initiated ENZA or ABI (September 2014 − May 2017) were included. The primary endpoint was a 4-point major adverse CV event (MACE; a composite of acute myocardial infarction, stroke, unstable angina/revascularization, and heart failure). Atrial fibrillation, venous thromboembolism, and all-cause death were also analyzed. Further, the risk of adverse CV outcomes was compared between ENZA- and ABI-treated cohorts (overall population and by CVD-risk subgroup). Sensitivity analysis was performed using a 5-point MACE (4-point MACE plus CV-related death) as the endpoint.</p> Results <p>Of 6319 patients (ENZA: 2934; ABI: 3385), 2913 propensity score-matched patients were included from each group (prior CVD: 76%). ABI was associated with a significantly higher risk of 4-point MACE (hazard ratio [HR]: 1.12; 95% confidence interval [CI]: 1.02–1.24; <i>P</i> = 0.028), unstable angina/revascularization (HR: 1.13; 95% CI: 1.01–1.26; <i>P</i> = 0.041), atrial fibrillation (HR: 1.73; 95% CI: 1.31–2.29; <i>P</i> &lt; 0.001), venous thromboembolism (HR: 1.37; 95% CI: 1.02–1.85; <i>P</i> = 0.037), and all-cause death (HR: 1.13; 95% CI: 1.07–1.19; <i>P</i> &lt; 0.001) versus ENZA. In the sensitivity analyses, these results were confined to the subgroup of patients with a history of CVD.</p> Conclusions <p>ABI-treated patients with mCRPC had a higher risk of developing composite 4-point MACE and other CV events than ENZA-treated patients.</p>