The study was conducted for the analysis of human papilloma virus in oral squamous cell carcinoma using p16. Material and methods:A total of sixty biopsied samples, embedded in paraffin and preserved in formalin, were obtained and histopathologically identified as OSCC. Four-micrometer serial sections had been cut, with one section undergoing H and E staining to determine the histological grades and the subsequent sections undergoing p16 IHC staining. Twenty of the sixty cases were well-differentiated (WDOSCC), twenty were moderately-differentiated (MDOSCC), and the remaining twenty were poorly-differentiated (PDOSCC) oral squamous cell carcinoma. To test the reliability of the IHC kit as well as the precision of the procedure, positive control slides of cervical cancer harbouring HPV were obtained. The main antibodies had been left out as a negative control. The occurrence of brown precipitate at the site of cytoplasm, nucleus or both had been suggestive of p16 positive immunoreactivity despite of staining intensity. Results: Out of 60 OSCC cases, 20 cases were Well differentiated OSCC, 20 were moderately differentiated OSCC and 20 were poorly differentiated OSCC. 1/20 well differentiated cases showed p16 positivity, 2/20 moderately differentiated cases showed p16 positivity whereas 3/20 poorly differentiated cases showed p16 positivity. In total,60 samples of OSCC were evaluated. The results revealed p16 positivity in 54 cases (90%) of 60. 6/20 poorly differentiated cases showed diffuse pattern of staining. 2/20 well as well as poorly differentiated cases showed patchy pattern of staining. 4/20 moderately differentiated cases showed patchy pattern of staining. 4/20 well differentiated cases showed rare singly dispersed cells. 1/20 moderately differentiated cases showed rare singly dispersed cells. Conclusion:A link between HPV as well as OSCC was found in this study. The PDOSCC was shown to have a diffuse staining pattern, which indicates an increase in viral burden and may be related to its aggressive character.