IMPORTANCE Optimizing radiation therapy techniques for localized prostate cancer can affect patient outcomes. Dose escalation improves biochemical control, but no prior trials were powered to detect overall survival (OS) differences. OBJECTIVE To determine whether radiation dose escalation to 79.2 Gy compared with 70.2 Gy would improve OS and other outcomes in prostate cancer. DESIGN, SETTING, AND PARTICIPANTS The NRG Oncology/RTOG 0126 randomized clinical trial randomized 1532 patients from 104 North American Radiation Therapy Oncology Group institutions March 2002 through August 2008. Men with stage cT1b to T2b, Gleason score 2 to 6, and prostate-specific antigen (PSA) level of 10 or greater and less than 20 or Gleason score of 7 and PSA less than 15 received 3-dimensional conformal radiation therapy or intensity-modulated radiation therapy to 79.2 Gy in 44 fractions or 70.2 Gy in 39 fractions. MAIN OUTCOMES AND MEASURES Time to OS measured from randomization to death due to any cause. American Society for Therapeutic Radiology and Oncology (ASTRO)/Phoenix definitions were used for biochemical failure. Acute (≤90 days of treatment start) and late radiation therapy toxic effects (>90 days) were graded using the National Cancer Institute Common Toxicity Criteria, version 2.0, and the RTOG/European Organisation for the Research and Treatment of Cancer Late Radiation Morbidity Scoring Scheme, respectively. RESULTS With a median follow-up of 8.4 (range, 0.02-13.0) years in 1499 patients (median [range] age, 71 [33-87] years; 70%had PSA <10 ng/mL, 84%Gleason score of 7, 57%T1 disease), there was no difference in OS between the 751 men in the 79.2-Gy arm and the 748 men in the 70.2-Gy arm. The 8-year rates of OS were 76%with 79.2 Gy and 75%with 70.2 Gy (hazard ratio [HR], 1.00; 95%CI, 0.83-1.20; P = .98). The 8-year cumulative rates of distant metastases were 4%for the 79.2-Gy arm and 6%for the 70.2-Gy arm (HR, 0.65; 95%CI, 0.42-1.01; P = .05). The ASTRO and Phoenix biochemical failure rates at 5 and 8 years were 31% and 20%with 79.2 Gy and 47%and 35%with 70.2 Gy, respectively (both P < .001; ASTRO: HR, 0.59; 95%CI, 0.50-0.70; Phoenix: HR, 0.54; 95%CI, 0.44-0.65). The high-dose arm had a lower rate of salvage therapy use. The 5-year rates of late grade 2 or greater gastrointestinal and/or genitourinary toxic effects were 21% and 12%with 79.2 Gy and 15% and 7%with 70.2 Gy (P = .006 [HR, 1.39; 95%CI, 1.10-1.77] and P = .003 [HR, 1.59; 95%CI, 1.17-2.16], respectively). CONCLUSIONS AND RELEVANCE Despite improvements in biochemical failure and distant metastases, dose escalation did not improve OS. High doses caused more late toxic effects but lower rates of salvage therapy.