Identification of a reliable biomarker for predicting prognosis in head and neck cancers is highly desirable and has long been sought. There have been several reports that members of the regenerating gene (REG) family are highly expressed in chronic inflammation and in tumors of the digestive organs. In addition, it has been described in several reports that REG expression is associated with the progression of digestive cancers. In the present study, we evaluated the effect of REG expression on the prognosis of hypopharyngeal cancer. We investigated 37 cases with hypopharyngeal squamous cell carcinoma, determined REG mRNA expression, which is easily detected in formalin-fixed paraffin-embedded tissues using the real-time reverse transcriptase-polymerase chain reaction method, and evaluated the survival rate using the Kaplan-Meier method. According to these results, REG III mRNA expression was significantly associated with prolonged survival. Therefore, we constructed hypopharyngeal cancer cell lines transfected with REG III and assessed the cell proliferation and chemosensitivity and/or radiosensitivity in vitro. Cells transfected with REG III exhibited significantly lower cell proliferation and higher chemosensitivity and/or radiosensitivity compared with the control cells. These data suggest that REG III may be a reliable biomarker of prognosis in hypopharyngeal cancer. This is the first report concerning the association of REG III expression and the prognosis of head and neck squamous cell carcinoma including hypopharyngeal cancer.