Introduction:Oral squamous cell carcinoma is usually preceded by potentially malignant disorders (PMDs), the most common being oral leukoplakia. A conservative management protocol is followed for milder dysplastic cases, while severe dysplastic lesions are surgically excised. Several classification systems have been developed based mainly on histopathological features with a lot of inter-observer variations. The present study was done to assess the use of immunohistochemical (IHC) markers in grading leukoplakic lesions in addition to histopathological grading.Aims and Objectives:To grade leukoplakia using different grading systems and assess if IHC markers can aid in categorizing leukoplakia.Materials and Methods:Thirty-five cases of leukoplakia were graded using Ljubljana, 2005 World Health Organization (WHO), and Binary System followed by IHC staining with p63 and CD31.Results and Statistics:Variation was noted in 12 cases while using WHO, 11 using Ljubljana, and 7 using Binary System and was significant on Cohen-Kappa statistics, with the least significant variation noted on Binary System. p63 staining assisted to group doubtful cases and even identify variation in cases graded positively on histopathology. In total, 17 cases stained one-third (mild/low), while 15 cases stained one-half or more (higher grade) epithelial thickness. A weak correlation was observed between all grading systems and p63 on Kendall's Tau-b analysis and the weak correlation was significant for the WHO and binary grading systems. Analyzing p63 and CD31 using Kruskal–Wallis test, an increase in mean vessel density (MVD) was noted for mild/moderate cases but decreased for severe cases.Conclusion:Addressing histological categorization of PMDs assisted by IHC markers to understand the biological behavior of the tissues is currently essential with studies on more markers to assist in the management protocol.