Frequent loss of fragile histidine triad (FHIT) expression in human gastrointestinal tract carcinomas has been reported; however, there were divergent opinions regarding FHIT expression in colorectal carcinoma. Recent studies have suggested that FHIT inactivation can be a consequence of defects in mismatch repair proteins, particularly mut S homolog 2 (MSH2). This study was designed to investigate the expression and clinical significance of FHIT and MSH2 proteins in human sporadic colorectal carcinoma (SCC).Immunohistochemistry SP method was used to determine the expression of FHIT and MSH2 in surgically resected specimens of 84 SCC and its corresponding paratumor normal colorectal tissues, and 23 cases of colonic adenomas.The positive expression rates of FHIT protein were 48.81%, 73.91%, and 100% in SCC, colonic adenomas, and adjacent normal colorectal tissues, respectively. The positive expression rates of FHIT protein showed increasing trend from SCC, colonic adenomas, to paratumor normal colorectal tissues; and the difference was statistically significant (P0.05), but were correlated with tumor invasive depth, differentiation degree, Dukes,stage, and lymph node metastasis (P< 0.05). The tumor tissues of deeper invade depth, lower differentiation degree, later Ducks,stage and with lymph node metastasis showed more reduction of FHIT protein expression. The expression level of MSH2 was only related to Dukes, stage (P< 0.05). FHIT expression was closely associated with MSH2 expression in SCC (r=0.3728,P< 0.01).(1) Loss or reduction of FHIT protein expression plays an important role in the development and progression of SCC. The expression levels of FHIT protein are related to the malignant degree of SCC and may be a valuable biological indicator for predicting the potent invasion and metastasis of SCC. (2) FHIT protein expression is in a positive correlation fashion with MSH2 protein expression in SCC.