OBJECTIVE Mutations of the p53 tumor suppressor gene can result in unregulated cellular growth and have been implicated in numerous malignancies. The objective of this study was to determine whether the detection of mutant p53 by immunohistochemical staining is predictive of progression in clinically localized adenocarcinoma of the prostate. METHODS Immunohistochemical staining for mutant p53 was performed on 40 formalin-fixed radical prostatectomy specimens. Benign glands in the sections served as controls. Immunoreactivity (IR) was categorized semi-quantitatively from 0 to 4+ (0 = no IR, 1+ = 1 % to 10%, 2+ = 11% to 40%, 3+ = 41 % to 70%, 4+ = 71 % to 100%). Results were then compared to Gleason score, Stage (T2 versus T3), surgical margins, lymph node and seminal vesicle involvement, age, race, preoperative prostate-specific antigen (PSA), and biochemical progression. Biochemical progression was defined as a persistently elevated postoperative PSA of 0.2 ng/mL or greater. RESULTS Thirty-two of the 40 tumors (80%) stained for mutant p53. None of the tumors that did not stain progressed, whereas 20 of 32 (62.5%) of the tumors that did stain progressed, with an overall mean followup of 50.8 months. Immunoreactivity did not correlate with any of the known prognostic variables but did have statistically significant correlation with progression by all three statistical methods used (Fisher's exact test, logistic regression, and log-rank test). CONCLUSIONS Strict quality control and newer antigen retrieval techniques reveal p53 abnormalities in many prostate cancers. Immunohistochemical detection of mutant p53 appears to be an independent predictor of progression. These data suggest potential utility of p53 as a preoperative prognostic indicator in localized prostate cancer.