Frequent loss of heterozygosity in head and neck squamous cell carcinoma (HNSCC) has been found in several chromosomal regions such as 3p, 9p, 11q, 13q and 17p. Fragile histidine triad (FHIT) gene is located at 3p14.2 encompassing a common fragile site, and is identified as a tumor suppressor gene. We examined 57 patients with HNSCC using immunohistochemistry, western blot, and reverse transcriptase polymerase chain reaction. The association between FHIT expression and clinicopathologic characteristics including p53 and Ki-67 expressions was analyzed. Immunohistochemical analysis revealed 30 patients (53%) of low FHIT expression and 27 patients (47%) of high FHIT expression. Low FHIT expression significantly correlated with high Ki-67 expression, indicating that tumor cells with low FHIT expression can proliferate aggressively. No correlation was found between FHIT expression and clinical characteristics including age, gender, tumor size, lymph node status, stage grouping, histologic grade, p53 expression, and prognosis. FHIT alteration may play an important role in cancer development of HNSCC, however it did not contribute to the prognosis.