Exposure to pollutants in the environment, tobacco and alcohol consumption, poor oral hygiene and opportunistic viral infections are important aetiological factors in head and neck cancers. In this study, we evaluate the complex interrelationships between these factors and molecular events such as p53 overexpression in causation of head and neck cancers. Tissue samples from 110 patients with histopathologically confirmed carcinoma of head and neck were analyzed from our tissue biorepository with patient consent. Data pertaining to their dietary habits, tobacco and alcohol consumption were abstracted. P53 overexpression was analysed by immunohistochemistry and HPV (high-risk genotype) were studied by Chromogenic in situ Hybridization using an ultra sensitive DNA probe. Chi-square analysis was done to determine relationships between proportions of dependent and independent variables. Bivariate relationships were determined between these variables using Spearman's rank correlation. Linear regression analysis was used to determine the best predictor variable influencing p53 expression. Tobacco consumption especially smoking cigarettes and all forms of tobacco consumption put together and HPV infection significantly influenced p53 overexpression. Forty-five percent of the studied cohort was positive for HPV. Regression analysis showed interaction between tobacco and HPV infection to be a primary predictor (β = 0.31, p = 0.02) for p53 expression. Tobacco in any form: chewing, smoking and snuffing, along with HPV infection is significantly associated with p53 overexpression. There is a high prevalence of HPV infection (45%) in Indian patients suggesting its possible role in the aetiology of head and neck cancer.