Objectives: We studied the role of minor mismatch repair proteins (MMR) human MutL homologue 1 (hMLH1) and human MutS homologue 2 (hMSH2) in the main subtypes of renal cell carcinoma (RCC). Methods: Expression of MMR proteins hMLH1 and hMSH2 were investigated in 166 RCC tumors, containing the main subtypes by immunohistochemistry. Furthermore, each tumor was screened for microsatellite instability (MSI) using the National Cancer Institute consensus panel for hereditary non-polyposis colon carcinoma as well as for elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) by 10 additional markers. Results: MSI was found only in 2.0% of analyzable cases and EMAST was detected only in 1 patient. hMLH1 and hMSH2 expression was reduced in 83.7 (118/141) and 51.2% (65/127) of cases, respectively, in a subtype-specific manner. None of the clear cell RCC tumors retained a high hMLH1 expression and 92.0% lost hMLH1 completely, while papillary and chromophobe RCC preserved the expression in 25.0 and 33.3% of cases (p < 0.001). Subtype specificity was also present in hMSH2 staining, where chromophobe RCC retained a high expression in 41.7% of cases, while clear cell and papillary tumors did not (29.9 and 23.1%; p = 0.01). Conclusion: MSI and EMAST are rare events in sporadic RCC, whereas diminished MMR protein expression is linked to tumor entity and might contribute to the different biological behavior of the RCC subtypes. Copyright (C) 2012 S. Karger AG, Basel