OBJECTIVE The aim of this study is to investigate the expression of p53 protein and Ki-67 antigen in normal oral mucosa and oral leukoplakia with different grades of dysplasia using immunohistochemistry and to clarify the correlation of the expression of these cell cycle regulatory proteins. METHODS A total of 20 archival tissue blocks obtained from our department which were diagnosed as mild (n = 5), moderate (n = 5), and severe dysplasia (n = 5) with normal mucosa (n = 5) as a control. Positivity of Ki-67 and p53 was analyzed using Statistical Package for the Social Sciences (IBM Corp. Released 2013. IBM SPSS Statistics for Windows, Version 22.0 Armonk, NY:IBM Corp) software. RESULTS All samples showed positive staining for p53 and Ki-67. Statistically significant difference (P < 0.05) was seen between the frequency of occurrence of p53 and Ki-67 pattern of expression among all the groups. The intensity of staining was mild to intense in basal layer as there was a progression toward the severity of the disease. Almost 81.1% correlation existed between p53 and Ki-67 with high correlation and marked relationship. CONCLUSIONS Oral leukoplakia represents the most common oral potentially malignant disorder (OPMD). Molecular biological markers such as p53 and Ki-67 are considered to be of great value in the diagnosis and prognostic evaluation of OPMD. Our results emphasize the potential use of p53 protein and Ki-67 antigen as significant molecular markers for early detection of PMDs and its risk of developing oral squamous cell carcinoma.