The FHIT gene is a candidate tumor suppressor gene that has been implicated in the development and progression of breast carcinoma. Recent studies have suggested that Fhit inactivation can be a consequence of defects in mismatch repair proteins, particularly Msh2. Fifty-three breast carcinomas were evaluated for Fhit and Msh2 expression by immunohistochemical staining. The same breast carcinomas were examined for allelic loss at three loci within or near FHIT by PCR-based microsatellite analysis. Seventeen of the 53 breast cancer cases were positive for Fhit protein, and 10 of the 43 informative cases showed FHIT loci deletion. Twenty-five of the 53 (47%) cases showed loss of Msh2 expression. No relationship between Msh2 protein loss and FHIT locus alteration or Fhit protein loss could be observed. Our results suggest that this mismatch repair protein may play little role in maintaining the integrity of the common fragile locus with the FHIT gene.