Amna H. E. Mohamed*, Wagdi  F.Ali  Elkashef**, Nagla M.Abd El-RazikSalama*** and Sherif Yousef M. El-Nagdy**** * Bachelor degree student, Faculty of Dentistry, Al Zawia University, Libya .  ** Assistant Professor of Pathology, Faculty of Medicine, Mansoura University, Egypt. *** Assistant Professor of oral Pathology, Faculty of Dentistry, Mansoura University, Egypt  . **** Professor and head of Oral Pathology, Faculty of Dentistry, Mansoura University, Egypt. Background:Oral squamous cell carcinoma (OSCC) is a malignant neoplasm derived from the stratified squamous epithelium of the oral mucosa. It accounts for more than 90% of malignant neoplasms of the oral cavity. In spite of large number of researches related to OSCC, uptill now the mechanism of its development and progression still unclear. It is important to study a new markers for better understanding of pathobiology of OSCC and better prediction of its prognosis. Aim of the study: This study aimed to evaluate any correlation between immunohistochemical expression of syndecan-1 and both of available clinical data and different histopathological grades of the studied OSCC cases. Results:Microscopical examination of OSCC cases revealed the different histological  features of differentiation and distribution of OSCC cells classified according to WHO into Well (21 cases), Moderately (13 cases) and poorly differentiated tumors (6 cases). Statistical analysis demonstrated that significant differences were observed between syndecan-1 expression and each of tumor size, clinical stages, histopathological grades and recurrence. No significant difference was found regarding either age, site, lymph node metastasis in relation to syndecan-1 expression. Furthermore, its expression was directly proportional to the degree of differentiation of the studied OSCC cases, its cytoplasmic expression pattern in the studied OSCC cases was more likely to be associated with a worse prognosis. Conclusions:The result of the present study suggest a possible role of syndecan-1 in early stages of oral carcinogenesis, as its down regulation is associated with high grades of OSCC cases as well as recurrence, thus it could be benefit as a marker for prediction of poor prognosis in this type of malignancy, moreover, it might also be helpful to select OSCC cases suitable for adjuvant chemotherapy before surgical interventions.