<p>Oral Squamous cell carcinoma (OSCC) is one of the most common head-neck cancers with significant morbidity and mortality. Previous studies showed stathmin over-expression in different poorly differentiated carcinomas including stomach, ovary and prostate. HR-HPV infection is an independent risk factor for OSCC and p16 is a surrogate marker. The aim of this study was to determine proportion of hyperplasia, dysplasia and OSCC cases in suspected oral squamous epithelial lesions and to evaluate the role of Stathmin and P16 in differentiating hyperplastic from dysplastic/OSCC cases along with their association with tumour grading. Biopsied specimens from suspected oral lesions were evaluated by routine histopathology and same blocks were used for immunohistochemistry with Stathmin and p16. This study included total 41 cases and showed 58.53% of the lesions are OSCC with male preponderance and buccal mucosa as the most common site.70.8% cases of OSCC showed p16 over expression. Both stathmin and p16 positivity have significant association with dysplastic and OSCC cases compared to hyperplasia with sensitivity of 75% for Stathmin and specificity of 92.31% for p16 to differentiate benign from premalignant/malignant cases. However there were no association with tumour grading. Hence Stathmin and p16 expression may be utilized in difficult cases to differentiate premalignant/malignant lesions from benign ones and targeted therapy may be developed in future. Higher proportions of p16 positive cases indicate the positive association between HR-HPV and OSCC. Further HPV-DNA based study may confirm the association and preventive measures can be implemented accordingly.</p>