BACKGROUND: The authors evaluated the long-term outcomes of men with prostate cancer and very high (> or =50 ng/mL) preoperative serum prostate-specific antigen (PSA) values that were treated with radical prostatectomy. METHODS: This study included 236 men with preoperative serum PSA values > or =50 ng/mL who underwent radical retropubic prostatectomy between 1987 and 2004. For comparison, the study cohort was divided into 2 groups: patients with PSA levels between 50 and 99 ng/mL and patients with PSA levels > or =100 ng/mL. Biochemical recurrence was defined as a single postoperative serum PSA value of 0.4 ng/mL or greater. Systemic disease progression was defined as the development of a local recurrence or systemic metastases, and any death resulting from prostate cancer or its treatment was defined as a cancer-specific mortality. RESULTS: Biochemical recurrence-free survival rates in the groups of patients with a PSA level 50 to 99 ng/mL and > or =100 ng/mL were 43% and 36% at 10 years, respectively. Systemic progression-free survival rates in the PSA 50 to 99 ng/mL and PSA > or =100 ng/mL groups were 83% and 74% at 10 years, respectively. Estimated overall cancer-specific survival was 87% at 10 years. CONCLUSIONS: Patients with prostate cancer and a serum PSA level > or =50 ng/mL have very high-risk prostate cancer that carries a high likelihood of being pathologically advanced. Although the probability of realizing long-term survival in these high-risk patients is less than in patients with more favorable disease, 10-year survival outcomes remain excellent and argue for aggressive management of these cases.