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Background: It has been emphasized that the molecular gatekeeper p53 has a key role in carcinogenesis and its mutation is seen in more than 50% of the human cancers including head and neck carcinomas and tobacco is the most important etiological agent in head and neck cancer. Aims: To assess p53 mutations in relation to tobacco usage in oral squamous cell carcinoma (OSCC) to understand the role of tobacco in the complex process of carcinogenesis. Materials and Methods: Forty formalin-fixed paraffin-embedded archival tissue samples were taken, of which 20 cases were associated with tobacco and 20 were not, and assessed immunohistochemically. Results: Enhanced expression of p53 was found to be associated with tobacco. Conclusions: p53 mutations are etiologically associated with the development of head and neck carcinomas and are associated with exposure to specific carcinogens of tobacco.