Background: Combined with RT, ADT is a highly effective and utilized treatment for men with localized PC, but some studies suggest that use of ADT leads to increased CVD. We explored the association between ADT and CVD in men receiving RT for localized PC in the National Program for Cancer Registry’s (NPCR) Breast and Prostate Cancer Patterns of Care (POC) study. Methods: From 7 population-based cancer registries, we constructed a sample of men with localized PC treated with definitive RT, stratified by race/ethnicity. Cases diagnosed in 2004 were followed through 2009. Comorbidity, at or before diagnosis, was quantified using the Adult Comorbidity Evaluation 27; subcategories were combined into CV disease (CVD = myocardial infarction, coronary artery disease, congestive heart failure, arrhythmia), CVD-equivalents (CVE = peripheral artery disease and stroke) and CV-risk factors (CVRF = hypertension, diabetes, obesity). Cause of death was determined from the National Death Index data and linkage with vital statistics data. Rates of CV death, in those receiving RT alone versus RT+ADT, were compared in univariate and multivariable analyses. Results: The sample included 2,413 men with mean age 67.7 years (range 39-94), 54.5% white non-Hispanic, 997 received RT alone and 1,416 received RT+ADT. Five-year CVD was 2.3% with RT alone and 3.4% with RT+ADT. In univariate analysis, the following predicted higher CVD with ADT: age < 60 (OR 1.42, p = 0.04), white (OR 2.06, p = 0.001), divorced/separated/widowed (OR 1.29, p = 0.02), insured by Medicare (OR 1.64, p = 0.04), living in mixed urban-rural area (OR 1.87, p = 0.03), higher education level (OR 1.56, p = 0.05), high socioeconomic status (OR 1.70, p = 0.03), no or mild comorbidity level (OR 2.14, p = 0.05 and OR 1.66, p = 0.02, respectively), low PSA (OR 5.44, p = 0,02), and Gleason score 3 (OR 2.12, p = 0.02). In multivariate analysis, use of ADT did not significantly predict hazard of death from heart disease (HR 1.21, p = 0.28) or PC (HR 0.76, p = 0.34). Conclusions: After controlling for confounding variables, use of ADT was not associated with increased risk of CVD in men receiving radiation as definitive therapy for localized PC.