Immunohistochemical stains are routinely used to detect abnormal DNA mismatch repair (MMR) protein expression in colorectal carcinomas, particularly when Lynch syndrome is suspected. Complete loss of MMR protein expression is often associated with underlying microsatellite instability (MSI), and the combined results of mutL homolog 1 (MLH1), postmeiotic segregation increased 2 (PMS2), mutS homolog 2 (MSH2), or mutS homolog 6 (MSH6) immunostains may point to the defective MMR protein in tumors with MSI. We have noted that some neoadjuvantly treated colorectal carcinomas display loss of MMR protein immunoexpression, despite a lack of underlying MSI and preserved staining in pretreatment tumor samples. The purpose of this study was to determine the frequency of this finding. We identified 51 neoadjuvantly treated resected colorectal cancers. Posttreatment tumor samples were immunohistochemically stained with MLH1, PMS2, MSH2, and MSH6 antibodies. Loss of staining for any marker was followed by analysis for MSI and assessment of MMR protein expression in pretreatment tumor samples. All of the 51 posttreatment tumor samples showed preserved MLH1, PMS2, and MSH2, but 10 posttreatment tumor samples (20%) showed decreased MSH6 staining. Of these, 9 posttreatment tumor samples displayed loss of staining in less than 100% of tumor cells, but preserved MSH6 expression in pretreatment tumor samples. One case showed a complete absence of MSH6 staining in both pretreatment and posttreatment tumor samples. All 10 cases were microsatellite stable. We conclude that extensive loss of MSH6 immunoexpression is common among neoadjuvantly treated colorectal carcinomas, but generally does not reflect underlying MSI. Therefore, diminished MSH6 staining in treated tumors should prompt immunohistochemical evaluation of pretreatment biopsy samples before genetic testing for Lynch syndrome.