Statement of the Problem: Oral squamous cell carcinoma (OSCC) is one of the most widely occurring cancers worldwide. Early diagnosis of primary tumors is the key to improve treatment outcome. Detecting cancer, determining prognosis, and monitoring disease progression or treatment response can be done based on molecular markers. CA19-9 is an isolated form of Lewis antigen. It is widely used for detecting pancreatic cancer in the clinical setting. P57 (KiP2) is a tumor suppressor gene. It is a positive regulator of cell proliferation, regulating proliferation through G1 phase by inhibiting cyclin dependent kinases. Its expression decreases in most malignancies. OSCC has variable differentiation grades and local invasion potential.Purpose: The aim of this study was to evaluate and assess the correlation of CA19-9 and P57 expression with invasive front and grade of OSCC.Materials and Method: This cross-sectional study was performed on forty paraffin blocks in three histologic grades; well, moderate, and poorly differentiated SCC. The two markers were assessed by immunohistochemistry methods (En vision). Proportional and total scores and staining intensity were measured for all samples.Results: CA19-9 staining was low in all three grades. The Kruskal Wallis test showed no significant correlation between tumor grade and CA19-9 expression; however, there was a significant difference between tumor intensity and margin intensity (p= 0.003). P57 staining was high in all three grades. The Kruskal Wallis test showed no significant correlation between tumor grade and P57 expression. There were no significant differences in total intensity of staining in margins of tumor (p= 0.85).Conclusion: Within the limitations of this study, it may be concluded that expression of CA19-9 and P57 cannot be used as determinants of tumor grade. Higher expression of CA19-9 in invasive front of SCC can be representative of local invasion and higher activity of tumor cells in the margins.