Genetic analysis of cervical cancer has demonstrated frequent allelic loss in the 3p chromosomal region. The newly described gene FHIT is located at chromosome region 3p14.2, and its expression has been demonstrated previously by reverse transcription-PCR to be abnormal in a majority of cervical cancer cell lines. In this study, 98 different lesions of the cervix were examined for Fhit expression by immunohistochemical staining. Whereas normal cervical epithelium demonstrated diffuse, moderate to intense cytoplasmic staining, many pathological lesions of the cervix displayed reduced or absent Fhit expression. Sixty-one percent of squamous carcinomas and 40% of adenocarcinomas of the cervix had abnormal Fhit expression. Sixty- five preneoplastic lesions of the cervix were examined. Eleven of 33 high- grade squamous intraepithelial lesions and 1 of 12 low-grade squamous intraepithelial lesions had abnormal Fhit expression. In summary, Fhit expression is frequently abnormal in both glandular and squamous cervical cancers, with a higher frequency of Fhit alterations observed in squamous lesions. In addition, abnormal Fhit expression can be detected in some preneoplastic lesions of the ectocervix. Alterations in Fhit expression may be an important marker of early progression in the development of cancers of the cervix.