Introduction: Oral squamous cell carcinoma (OSCC) accounts for about 90% to 95% of all malignancies of the oral cavity.The majority of OSCCs are preceded by oral potentially malignant disorders (OPMDs). Podoplanin (PDPN) is a mucin-like small transmembrane glycoprotein. Alterations in PDPN immunoexpression have been reported in OPMDs and OSCCs.Objective: The objectives of this study were to evaluate the role of PDPN immunoexpression in oral leukoplakia (OL) and different histological grades of OSCC and to assess the role of PDPN as a potential biomarker for predicting the risk of malignant transformation.Materials and methodology: Immunohistochemical analysis for PDPN was performed in 45 histologically confirmed cases of formalin-fixed, paraffin-embedded specimens of different grades of OSCCs and 15 cases of OLs with 15 cases of the normal oral mucosa (NOM) as controls. The expression and distribution of this marker were analyzed in these lesions.Results: The immunoexpression of PDPN showed a significant increase in the expression of the percentage of positive cells, staining intensity, location of staining in the epithelium, tumor islands, and within the cells, as well as the mean lymphatic micro vessel density between NOMs, OLs, and different grades of OSCCs.Conclusion: Upregulation of PDPN can be related to the malignant transformation of OLs and biological aggressiveness of OSCCs. The enhanced immunoexpression of PDPN signifies that this immunomarker can have a role in tumor cell differentiation and the neoplastic progression of OSCCs. Increased density of lymphatic vessels suggested an important role of lymphangiogenesis in tumor progression and also as a prognostic factor for lymph nodal metastasis.