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Oral cancers of tobacco and betel chewers represents a unique in-vivo model to understand the genotoxic effect of tobacco and betel carcinogens on oncogenes and tumor suppressor genes. Coordinated interactions of p53 and MDM2 play an important role in regulation of critical growth control gene following exposure to DNA damaging agents. The purpose of this study is to determine if the tumor suppressor function of p53 is inactivated by mutation or other alternative mechanisms in carcinogen-induced oral squamous cell carcinoma (SCC), and to investigate the clinicopathological significance of p53 and MDM2 expression. The p53 mutation in oral SCC of tobacco and betel chewers (n=40) was detected by polymerase chain reaction - single strand conformation polymorphism (PCR-SSCP) analysis and immunohistochemistry (IHC) was done to investigate p53 and MDM2 proteins overexpression. The incidence of p53 mutation was relatively low (17.5%), but there was a high prevalence of MDM2 overexpression (72.5%). In the total of 40 cases, IHC phenotype showed p53 positive immunostaining with MDM2 positive immunostaining (p53+/MDM2+) 62.5%, p53 negative immunostaining with MDM2 negative immunostaining (p53-/MDM2-) 15%, p53 positive immunostaining with MDM2 negative immunostaining (p53+/MDM2-) 12.5%, and p53 negative immunostaining with MDM2 positive immunostaining (p53-/MDM2+) 10%. A significant correlation was found between MDM2 and p53 overexpression (p=0.0289). Moreover, p53+/MDM2+ phenotype was significantly associated with poorly differentiated tumors (p=0.0007). These results conclude that other factors than p53 mutation is likely to be the targets of tobacco/betel carcinogens and MDM2 may play an important role in tobacco/betel chewing-related oral SCCs. Overexpression of MDM2 protein may constitute an alternative mechanism for p53 inactivation.