Oral squamous cell carcinoma (OSCC) is a world-wide health problem and its incidence accounts for 1.9-3.5% of all malignant tumors. Transforming growth factor beta/Smads (TGF-beta/Smads) signaling pathway plays an important role in oncogenesis, but its function and molecular mechanisms in OSCC remain unclear. Expression of transforming growth factor-beta receptor type II (TbetaRII) and Smad4 was studied by immunohistochemistry in 108 OSCC patients and 10 normal controls. Function and molecular mechanisms of TGF-beta/Smads signaling pathway was then investigated in two human tongue squamous carcinoma cell lines with high and low metastasis (Tb and Tca8113) by RT-PCR, Western Blot, immunofluorescence, cell growth curve and flow cytometry (FCM), respectively. TbetaRII and Smad4 were significantly down-regulated in tumor tissues (with or without lymph node metastasis) compared to normal oral epithelium tissues (P < 0.05). TGF-beta1 induced arrest of the cell cycle rather than cell death in Tca8113 and Tb cells, and this influence was mediated by the increasing the expression and changing the location of its downstream components of TGF-beta1/Smads signaling pathway. TGF-beta1 rapidly increased the expression of p15 and p21 in both Tca8113 and Tb cells. TGF-beta1 did not increase p27 expression in Tca8113 cells, but p27 expression was increased in Tb cells. These indicated that TGF-beta1 induced G(1) arrest of cell cycle through a different regulating pathway in Tb cells compared with Tca8113 cells. Thus, we conclude that TGF-beta/Smads signaling pathway play a important role on cell growth and metastasis potential in OSCC.