BACKGROUND: Mismatch repair (MMR) genes are responsible for coordinated correction of misincorporated nucleotides formed during DNA replication. Inactivating mutations in MMR genes have been described in sporadic cancers and a hereditary cancer predisposition syndrome. Mismatch repair deficiency causes instability at microsatellites and increased mutation rates. Although microsatellite instability (MSI) has been described in high-grade and lymph node positive prostate carcinoma specimens, an analysis comparing hMSH2 expression, MSI, and outcome in clinically organ confined prostate carcinoma has not been reported. METHODS: Immunohistochemical analysis of benign and malignant prostate tissue from 101 patients was performed using a monoclonal antibody specific for the hMSH2 protein. Expression was correlated with MSI using dinucleotide repeat markers and laser-captured microdissected DNA from normal and tumor cells. hMSH2 protein expression and MSI were assessed with respect to pathologic stage, Gleason score, and time to detectable serum prostate specific antigen (PSA) after prostatectomy in patients with clinically localized prostate carcinoma. RESULTS: In normal glands, hMSH2 staining was minimal to low and confined to the basal cell layer. In 32% of benign prostatic hyperplasia cases, hMSH2 staining was increased in the basal and luminal cell layers whereas 71% of cancer specimens had uniform moderate to high staining. Microsatellite instability was detected in 60% of absent to low staining and 26% of moderate to high staining prostate carcinoma specimens. Differential staining in benign versus malignant prostate tissues was statistically significant (P < 0.001) as was the correlation between absent to low hMSH2 staining and presence of MSI (P = 0.028). Decreased risk for PSA recurrence after radical prostatectomy correlated with absent to low hMSH2 staining in malignant prostate tissue but was only marginally significant (P = 0.05 for 24 month recurrence and P = 0.08 for overall time to PSA recurrence). CONCLUSIONS: The results of the current study demonstrate differential hMSH2 expression in benign and malignant prostate tissue. Moreover, hMSH2 expression is altered in a subset of clinically localized prostate carcinoma specimens independent of pathologic stage and Gleason pattern. A statistically significant correlation between hMSH2 immunohistochemical staining intensity and MSI also was identified in prostate carcinoma specimens. Furthermore, the time to cancer recurrence as determined by detectable serum PSA after prostatectomy was associated with hMSH2 staining intensity. Taken together, our results suggest that hMSH2 gene expression in prostate carcinoma may be a useful prognostic marker for outcome in men with clinically organ confined prostate carcinoma.