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| High-risk prostate cancer can be defined by the assessment of pretreatment prognostic factors such as clinical stage, Gleason score, and PSA level. High-risk features include PSA >20 ng/ml, Gleason score 8–10, and stage T3 tumors. Patients with adverse prognostic factors have historically fared poorly with monotherapeutic approaches. Multimodal treatment utilizing combined androgen suppression and radiotherapy has improved survival rates for patients with high-risk prostate cancer. In addition, multiple randomized trials in patients treated with primary radical prostatectomy have demonstrated improved outcomes with the addition of adjuvant radiotherapy. Improved radiotherapy techniques that allow for dose escalation, and new systemic therapy approaches such as adjuvant chemotherapy, present promising future therapeutic alternatives for patients with high-risk prostate cancer.