73 Background: Radiation therapy is commonly employed for localized prostate cancer; however, there is little data regarding the comparative effectiveness of radiation therapy (RAD) vs. conservative management (CM). Methods: We performed a population-based cohort study, using Medicare claims data linked to the Surveillance, Epidemiology, and End Results data, to evaluate outcomes in 42,039 men aged 65-85 years treated with either primary RAD or CM for T1-T2 prostate cancer diagnosed in 1992-2005. To overcome potential biases associated with unmeasured confounding variables, we used instrumental variable analysis (IVA), a pseudo-randomization technique that captures the randomness associated with geographic variations in the use of RAD, to control for overt and hidden confounders. Results: The majority of patients (57%) had low-risk disease (Gleason score ≤7, PSA <10, and T stage ≤T2a), and RAD was commonly used (60%) with considerable geographic variations. With median age 74 years and median follow-up 119 months, higher RAD use was not associated with improved survival in low-risk patients (10-year disease-specific survival differed by −0.9%, 94.9% vs. 95.8% in the highest and lowest tertile RAD use areas respectively; 95% C.I. −.1 to 0.6%). Among high-risk patients (Gleason score >7 or PSA >20), highest tertile RAD areas showed a borderline improved (2.7%) 10-year disease-survival (83.9% vs. 81.2% in the highest and lowest tertile radiation use areas; 95% C.I. −1.1% to 7.0%). The results in the moderate-risk group were between that of the low- and high-risk group. Primary RAD did not reduce future ADT use (odds ratios 0.95 for low-risk, 1.02 for moderate-risk, and 1.07 for high-risk with corresponding P values of 0.50, 0.86, and 0.51, respectively). Conclusions: In patients aged over 65 years old with low-risk prostate cancer, primary RAD is unlikely to improve 10-year disease-specific survival or prevent future ADT use. Weighing the potential risks and benefits of radiation therapy is critical for decision making. No significant financial relationships to disclose.