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Introduction: Head and Neck Squamous Cell Carcinoma (HNSCC) is the sixth most common cancer globally and the seventh most common cause of cancer-related mortality. Tobacco use, alcohol consumption, and Human Papillomavirus (HPV) infection are prominent risk factors for HNSCC. HPVpositive Oral Squamous Cell Carcinoma (OSCC) differs from HPV-negative OSCC in terms of risk factors, preferential site of origin, age, histomorphological features, molecular genetic alterations, and prognosis. The prominent basaloid morphology and lobular growth of OSCCs are associated with p16 positivity and p53 negativity, respectively. Aim: To establish the immunohistochemical expression of p16 (p16INK4a) and p53 in OSCC and to assess their relationship with specific histomorphological features, in the form of solid growth of cells in a lobular configuration, small crowded cells with scant cytoplasm, dark hyperchromatic nuclei without nucleoli. Materials and Methods: The cross-sectional study involved fifty cases of OSCC over a two-year period from January 2017 to January 2019 at Army Hospital (R and R) Delhi Cantt. The intensity of p16 and p53 protein expression was graded as follows: no staining (0), weak staining (1), moderate staining (2), and strong staining (3). The proportion/percentage of staining for p16 and p53 protein expression was calculated as follows: 1-4% (1), 5-19% (2), 20-39% (3), 40-59% (4), 60-79% (5), and 80-100% (6) cells stained. A quick score of 0-1 (negative), 2-3 (weak positive), 4-5 (moderate positive), and >6 (strong positive) was assessed. Cross tables were generated and the Chi-square test was used for testing associations. The Statistical Software for Data Science (STATA)-14 was used for statistical analysis. Results: A total of 50 cases of OSCC were analysed for histomorphological features and immunohistochemical patterns of p16 and p53. The age distribution showed that 8 (16%), 9 (18%), 18 (36%), 13 (26%), and 2 (4%) of the patients were in the age groups of 31-40 years, 41-50 years, 51-60 years, 61-70 years, and above 70 years, respectively. The gender distribution noted 42 (84%) males and 8 (16%) females. Genital and nongenital mucosa are usually involved by HPV subtypes 6, 11, 16, 18, and 16, 18, 11, 13, 2, respectively. HPV-16 has been demonstrated in 90-95% of all HPV-positive HNSCC cases, followed by HPV-18, HPV-31, and HPV-33. p53 is considered the guardian of the genome and controls the expression and activity of proteins involved in cell cycle regulation, DNA repair, cellular senescence, and apoptosis. More than 50% of all primary HNSCC exhibit p53 mutation. Conclusion: A significant correlation was observed between age, dysplasia, keratinisation, basaloid morphology versus p16 expression, and lobular growth, histological grade versus p53. An inverse relationship between p16 and p53 expressions was observed. The immunohistochemical expression of p16 as an immunohistochemical marker of HPV, along with p53, is recommended. Due to the constraint of the study period, the survival of the patients could not be assessed in correlation with p16 and p53 expression.