Introduction:Oral squamous cell carcinoma (OSCC) is the most common malignant tumor occurring in the oral cavity.Aim:The present study was conducted to evaluate the biomarkers such as epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2/neu), p53 and Ki67 expression in OSCC cases, and its correlation with other well-established clinicopathological parameters.Materials and Methods:Seventy cases of OSCC cases diagnosed between 2015 and 2019 were included in the study. A technique of manual tissue microarray was employed for the analysis of expression of IHC markers such as EGFR, HER2/neu, p53, and Ki67 in all cases. Results were subjected to the statistical analysis.Results:A statistically significant positive association was noted between EGFR expression and tumor grade, tumor stage, and p53 immunoexpression in OSCC cases. Increased EGFR expression was noted insignificantly in OSCC cases with lymph node (LN) metastasis and Ki67 positive cases. Statistically significant positive association was noted between HER2/neu expression and tumor grade and stage of oral SCC cases. Increased HER2/neu expression was noted insignificantly in OSCC cases with LN metastasis, p53 and Ki67 positive OSCC cases. A statistically significant positive association was noted between percent of tumor cells expressing EGFR, HER2/neu, p53 and Ki67, and grade of OSCC.Conclusion:This study intends to document prognostic utility of EGFR and HER2/neu expression in OSCC cases in the Indian setting and contribute to the data pool which could aid in formulating individual tailored therapy that includes targeted therapy in oral SCC cases.