Squamous cell carcinoma (SCC) is the most common type of oral cancer. Malignant epithelal cells undergo cytological changes by a process referd to as epithelial mesenchymal transition (EMT). The cancer associated fibroblasts (CAFs) in the tumor micro-environment are now the focus of intense research and are believed to correlate with poor prognosis. They are characterized by alpha smooth muscle actin (α-SMA) expression, which is a myofibroblastic marker. Physiologically myofibroblasts are not as abundant as fibroblasts in the oral cavity, they have limited locations such as blood vessels walls in the oral mucosa. Aim: evaluation of the potential role of α-SMA in the progression of SCC. Materials and methods: qRT-PCR was performed to evaluate α-SMA gene expression in tongue SCC cell line (SCC 25), normal fibroblasts cell line (Wi-38) and in a coculture of both cells. Qualitative and quantitative immunohistochemical analysis of α-SMA expression with clinico-pathological correlations was performed for 24 SCC specimens of different grades. Results: qRT-PCR results showed that there was α-SMA expression in the epithelial cells, and that co-culturing resulted in an overall increase in α-SMA expression. Immunohistochemical evaluation of the specimens revealed that the expression of α-SMA increased with tumor grade and correlated with lymph node involvement. Conclusion: α-SMA can be used as a prognostic marker and a potential target for cancer therapy.