AIM: Oral squamous cell carcinoma (OSCC) may be preceded by potentially malignant disorders such as leukoplakia and oral submucous fibrosis (OSF). p63 in concert with p53 regulates cell proliferation and differentiation and may have a role in potentially malignant and malignant lesions of the oral cavity. The aim of the study was to evaluate and compare the expression of p53 and p63 proteins in OSCC, leukoplakia, and OSF by immunohistochemistry (IHC). METHODS: Tissue sections of OSCC (n = 20), leukoplakia (n = 20), OSF (n = 20) and normal oral mucosa (n = 10) were stained with p53 and p63 antibodies by IHC. Mean labeling index (LI) among the study groups were compared using the Kruskal-Wallis test. RESULTS: The mean LI of p53 for OSCC, leukoplakia, OSF, and normal mucosa were 56.9 +/- 21.3, 37.6 +/- 12.6, 34.6 +/- 8.7 and 15.1 +/- 9, while mean LI of p63 were 56.8 +/- 19.6, 42.3 +/- 10.5, 32.8 +/- 12.1, and 26.4 +/- 9.4. The mean LI of p53 and p63 were significantly higher in OSCC, leukoplakia and OSF compared to normal mucosa (P < 0.01; P < 0.01). CONCLUSION: The significant increase in expression of p53 and p63 proteins in OSCC, leukoplakia, and OSF suggests their role as surrogate markers of malignant transformation.