18 Background: Androgen deprivation therapy (ADT) is associated with greater risk of diabetes and coronary heart disease in men with prostate cancer but there is significant controversy surrounding its potential impact on cardiovascular mortality especially among men with lower rates of cancer-specific death. We assessed the relationship between ADT and mortality in a large randomized trial of men treated with or without short-course ADT and radiation therapy (RT) for clinically-localized prostate cancer. Methods: Between 1994-2001, 1979 eligible men (median age 71) with clinically-localized (T1-2, PSA<20) prostate cancer were enrolled on a phase III trial (RTOG 94-08) and randomized to RT and 4 months of neoadjuvant/concurrent ADT or RT alone. Fine-Gray proportional hazards model was used to evaluate the relationship between treatment arm and mortality (disease-specific and cardiovascular). Covariates included PSA, Gleason score, T-stage, age, race, weight, prevalent cardiovascular disease (CVD), diabetes (DM), and hypertension. Results: After a median follow-up of 8.2 years, use of ADT improved overall and disease-specific survival but there was no ADT-related increase in cardiovascular mortality or non-prostate cancer death. There were a total of 191 cardiovascular-related deaths. At 10-years, cardiovascular mortality for men treated with RT+ADT was 9.8% vs 10.7% for men treated with RT alone. In multivariate analyses, treatment arm was not significantly associated with an increased risk of cardiovascular mortality [adjusted hazard ratio (HR)=0.93, 95% confidence interval (CI) 0.69-1.26, p=0.64]. Traditional cardiac risk factors, including prevalent CVD and DM, were significantly associated with greater cardiovascular mortality. Results were similar when limiting analyses to patient subsets at high risk for cardiovascular mortality and at low risk for disease-specific mortality. Conclusions: Use of short-course ADT improves overall and disease-specific survival but does not appear to increase cardiovascular mortality in men with clinically-localized prostate cancer. Supported by RTOG grant U10 CA21661 and CCOP grant U10 CA37422 from NCI.