Oral leukoplakia (OL) may precede squamous cell carcinoma and its histologic grading is subjective. Loss of heterozygosity (LOH) has been reported as risk predictor of OL malignant transformation. Objective: Correlate histologic and immunohistochemical characteristics of OL and evaluate molecular aspects, aiming at to demonstrate their malignant potential. Study Design: Ninety-six cases of OL were stratified by the World Health Organization (WHO) and Kujan systems by 3 blinded pathologists and correlated to the immunohistochemical biomarkers (IBs) p53, Ki-67, pRb, and p16. In 25 cases, LOH analysis was performed. Results: A moderate concordance among pathologists in both systems (Kendall correlation) was observed. Weak to moderate correlation among IBs was observed, as well as among IBs and histologic grading (Spearman correlation). Staining for p16 showed agreement with all the others IBs. Ki-67 was the most concordant marker in Kujan's system. The LOH was found in moderate and severe dysplasia for the markers TP53 (17 p13.1) and IFNA (9 p21), in 2 cases each. Conclusions: Greater concordance among pathologists as well as between histologic grading and IBs was demonstrated by Kujan's system. In OL, p16 can express alone the diagnoses obtained by all others IBs together. LOH could be related to the degree of histopathologic severity and to the greater expression of IBs.