PURPOSE Radiotherapy (RT) plus long-term androgen suppression (AS) are a standard treatment option for patients with high-risk localized prostate cancer. We hypothesized that docetaxel chemotherapy (CT) could improve overall survival (OS) and clinical outcomes among patients with high-risk prostate cancer. PATIENTS AND METHODS The multicenter randomized NRG Oncology RTOG 0521 study enrolled patients with high-risk nonmetastatic disease between 2005 and 2009. Patients were randomly assigned to receive standard long-term AS plus RT with or without adjuvant CT. RESULTS A total of 612 patients were enrolled; 563 were evaluable. Median prostate-specific antigen was 15.1 ng/mL; 53% had a Gleason score 9 to 10 cancer; 27% had cT3 to cT4 disease. Median follow-up was 5.7 years. Treatment was well tolerated in both arms. Four-year OS rate was 89% (95% CI, 84% to 92%) for AS + RT and 93% (95% CI, 90% to 96%) for AS + RT + CT (hazard ratio [HR], 0.69; 90% CI, 0.49 to 0.97; one-sided P = .034). There were 59 deaths in the AS + RT arm and 43 in the AS + RT + CT arm, with fewer deaths resulting from prostate cancer in the AS + RT + CT arm versus AS + RT (23 v 16 deaths, respectively). Six-year rate of distant metastasis was 14% for AS + RT and 9.1% for AS + RT + CT, (HR, 0.60; 95% CI, 0.37 to 0.99; two-sided P = .044). Six-year disease-free survival rate was 55% for AS + RT and 65% for AS + RT + CT (HR, 0.76; 95% CI, 0.58 to 0.99; two-sided P = .043). CONCLUSION For patients with high-risk nonmetastatic prostate cancer, CT with docetaxel improved OS from 89% to 93% at 4 years, with improved disease-free survival and reduction in the rate of distant metastasis. The trial suggests that docetaxel CT may be an option to be discussed with selected men with high-risk prostate cancer.