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Purpose HPV is believed to promote the oncogenic process, and the correlation between viral oncoproteins and dysfunction of p16(INK4A) tumor suppressor protein in oral lesions is controversial. Results from recent studies suggest that some of these cancers, primarily those of the oropharynx (and, more specifically, those of the base of the tongue and the tonsils), are associated with infection with high-risk HPV types. The aim was to compare and correlate the P16 protein expression between the oral and oropharyngeal SCCs. Material and Methods Forty-six formalin-fixed and paraffin-embedded biopsy specimens were obtained from the Oral Pathology department, V.S.dental college and hospital, Bangalore and from General Pathology, KIMS, Bangalore. All the samples were archival specimens. Tissues were sectioned and histopathological diagnoses were reconfirmed by two experienced professionals. Of the 46 lesions, 20 were oral SCCs, and twenty were from the oropharyngeal carcinomas. Six controls were used, 3 positive control, i.e., cases from cervical carcinoma and three negative controls, i.e cases from normal oral mucosa, and were subjected to IHC. The IHC expression of p16 was quantified in a double-blind protocol and classified according to nuclear and cytoplasmic positivity. The scoring was considered as positive when more than 5% cells (cut-off) stained positively, and was graded as described by Klaes et al. A correlation between p16 expression and histopathological features was done. Results Fourteen (70%) of 20 oralpharyngeal lesions were p16-positive and 8 (40%) of oral lesions were p16 positive. The IHC expression results were analyzed by the probability tests, with (P less than 0.05) being considered statistically significant. Conclusions These results showed overexpression of p16 protein in oral and oropharyngeal lesions, more so in the latter and this has to be correlated with HPV association to suggest that p16 may serve as a biomarker in oral and oropharyngeal cancer.