Introduction:Oral cancer ranks third among all cancers in the Indian population with approximately 45% of call cancer cases in India being diagnosed as oral cancer, among which 20%–50% of the cases are observed to be associated with human papillomavirus (HPV) infection.Aim:This study aims to detect and evaluate the presence of p16 in oropharyngeal squamous cell carcinoma (OPSCC) patients using immunohistochemistry (IHC).Materials and Methods:This study was based on samples collected from 21 patients with primary OPSCC who were diagnosed and treated during the period of December 2017–March 2018. Inclusion criteria were complete clinicopathologic data, adequate clinical follow-up, and availability of sufficient paraffin-embedded tumor material. HPV immunoreactivity was further investigated by means of IHC using p16 as a marker.Results:IHC results revealed p16 positivity in six OPSCC cases. There was no statistically significant association of the p16 positivity of HPV with the age, gender, or site.Conclusion:Our results suggest that IHC-based detection of p16 provides a suboptimal prognostic information if not combined with detection of HPV DNA. Although p16 expression and HPV DNA infection are correlated with HPV-associated OPSCCs, neither of the tests alone is the optimal method for HPV status detection.