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Objectives: It has been hypothesized that abnormal p53 protein expression is associated with a worse prognosis after radiation (RT) and androgen suppression therapy (AST). This hypothesis was prospectively tested. Methods: Between May 1997 and April 2001, 180 men with clinical stage T1c-T3cN0M0 adenocarcinoma of the prostate were registered on a study evaluating whether the endorectal magnetic resonance imaging (eMRI)-defined change in tumor volume (TV) during neoadjuvant (n) AST was associated with prostate-specific antigen (PSA) outcome. Of these, 141 had sufficient tissue to perform immunohistochemical detection of the p53 protein expression status and 113 had complete eMRI information. Multivariable Cox regression analysis was used to assess whether p53 protein expression status predicted time to PSA failure adjusting for known prognostic factors. Results: After a median follow-up of 6.9 years and adjusting for PSA level, Gleason score, clinical stage, and eMRI-defined TV change during nAST, men with abnormal compared with normal p53 expression were at increased risk of PSA failure (hazard ratio [HR]: 2.8; 95% confidence interval [CI]: 1.3–5.9; P = 0.008 for the 141; HR: 2.4; 95% CI: 1.1–5.4; P = 0.03 for the 113). Adjusted estimates of PSA failure were significantly higher (P = 0.03) in men with abnormal compared with normal p53 expression. At 5 years, these respective estimates were 33% and 18%. Conclusions: Maximizing local control and randomized trials evaluating the impact on survival of adding novel agents to maximal local therapy are warranted in men whose prostate cancer demonstrates abnormal p53 expression. [Copyright &y& Elsevier]