Frequent loss of Fhit expression has been reported in human gastrointestinal tract carcinomas; opinions remain divergent regarding Fhit expression in colorectal carcinoma (CRC) cases. Recent studies have suggested that Fhit inactivation can be a consequence of defects in mismatch repair proteins, particularly Msh2. Immunohistochemical analysis of Msh2 and Fhit protein expression in 62 CRC cases was performed. The same CRCs were examined for allelic loss at three loci within or near FHIT and for FHIT mRNA expression by reverse transcription-PCR amplification. Half of the 62 CRC cases were positive for Fhit protein. Fhit protein loss correlated significantly with the progression of carcinoma (P < 0.01) as well as lymph node metastasis (P < 0.05). Loss of Msh2 protein correlated significantly with loss of Fhit protein (P < 0.05) and FHIT locus alteration (P < 0.05). Loss of Fhit protein expression was observed in 50% of sporadic CRCs and was significantly more frequent in more advanced cancers. Interestingly, alteration of the fragile FHIT locus and loss of Fhit protein expression were significantly more frequent in sporadic CRCs lacking Msh2 protein, suggesting that this mismatch repair protein may be important in maintaining the integrity of the common fragile locus within the FHIT gene.