Although many investigators have studied on the development of oral squamous cell carcinoma (OSCC), the data about the molecular mechanism remains fragmented. Objective: To investigate the expression of a signaling molecule of TGF-beta pathway, Smad4 in OSCC and normal oral mucosa. Methods: The expression of Smad4 in tissue samples of OSCC and oral normal mucosa was studied by means of immunohistochemical technique. Eleven paraffin-embedded tissue samples of OSCC and nine paraffin-embedded tissue samples of oral normal mucosa were collected and investigated. Results: The rate of Smad4 expression in OSCC tissue samples was only 45.5% while 88.9% in tissue samples of normal oral mucosa. In Smad4-positive cases of OSCC, the protein was expressed mainly in the cytoplasm of the tumor cells. In Smad4-positive oral normal mucosa, the protein was strongly expressed in the basal and spinous cell layers. Conclusions: These findings indicate that the aberration of TGF-beta pathway as evidenced by a reduction of Smad4 expression may promote carcinogenesis of OSCC.