Late-diagnosis of malignant potentiality of oral precancers like Oral Sub-mucous Fibrosis (OSF) contributes towards high mortality of oral cancer patients. Current study intends to differentiate Normal Oral Mucosa (NOM) from OSF stages in terms of expression of a prime candidate gene (p63), correlated with epithelial proliferation and maturation, for better assessment of malignant potentiality of the pre-cancer. Fifty three oral biopsies (i.e. 8 NOM, 45 OSF patients with and without dysplasia) were histopathologically evaluated by hematoxylin and eosin, whereas, p63+ nuclei were identified immunohistochemically. The differences in cellular arrangement, especially in epithelial basal layer of diseased epithelium were observed. In respect to p63 expression the percentage of nuclei positive to this molecule and their size were studied. The p63 expression was higher in dysplastic epithelium and distribution of p63+ cells and their nuclear shape features demonstrated remarkable differences between NOM and OSF stages. © 2010 IEEE.