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The role of neoadjuvant androgen deprivation (NAD) in high-risk prostate cancer patients receiving high-dose radiotherapy (RT) remains unstudied. To evaluate the effect of a course of NAD, we reviewed the experiences of three institutions treating these patients with combined RT and high-dose rate brachytherapy (HDR). Of 1260 prostate cancer patients with high-risk features (pretreatment prostate-specific antigen (PSA) X10, Gleason Score (GS) X7, or T stage XT2b), 560 received no NAD (n ¼ 308) or NAD for p6 months (n ¼ 252). Median dose to the prostate from RT and HDR was 42 and 23 Gy, respectively. Average total biologic equivalent prostate dose was 4100 Gy (a/b ¼ 1.2). Median follow-up was 4.3 years. Pretreatment characteristics were similar on v 2 tables for all 560 patients treated with or without NAD including pretreatment PSA (P ¼ 0.11), GS (P ¼ 0.4), and clinical T stage (P ¼ 0.2). Outcomes worsened for patients receiving NAD (5-year distant metastasis (DM) 10 vs 5% (P ¼ 0.04); cause-specific survival (CSS), 93 vs 98% (P ¼ 0.005)).Higher 5-year DM rates and lower CSS occurred in NAD patients with a GS between 8 and 10 (n ¼ 112 (P ¼ 0.03, P ¼ 0.02)), pretreatment PSAX15 (n ¼ 136 (P ¼ 0.03, P ¼ 0.008)), and palpable disease XT2a (n ¼ 434 (P ¼ 0.04, P ¼ 0.02)). The only two significant risk factors for DM on Cox multivariate analysis were GS (P ¼ 0.003, HR 2.8) and NAD (P ¼ 0.03, HR 2.7). AD given before definitive high-dose RT did not benefit prostate cancer patients with intermediate-and high-risk features. We favor the use of concurrent/adjuvant AD over prolonged NAD for prostate cancer patients for whom AD is clinically indicated.