Abnormal expression of the fragile histidine triad (FHIT) candidate tumor suppressor gene has been observed in a variety of human tumors, but little is known about its expression during colorectal tumorigenesis. Sections of 70 aberrant crypt foci (ACF), 55 adenomas, 84 primary colorectal carcinomas, and 13 metastatic lesions were evaluated immunohistochemically for Fhit expression. All normal colonic epithelium showed a strong expression of Fhit; 44% of carcinomas showed a marked loss or absence of Fhit expression. The proportion of carcinomas with reduced expression showed an increasing trend (a) with decreasing differentiation and (b) in tumors with metastases (62%) compared with tumors without metastases (38%). The proportion of metastatic lesions (12 of 13) with reduced expression of Fhit was even greater. Although only a small proportion of ACF and adenomas showed a reduction of Fhit expression, the reduced expression of Fhit was strongly associated with the degree of dysplasia in both ACF (P = 0.0002) and adenomas (P = 0.0085). The findings of reduced expression of Fhit in a small proportion of colonic precancerous lesions and in increased proportions of primary and metastatic colorectal cancers suggest that Fhit plays a role in the development and progression of some colon carcinomas.