INTRODUCTION: Oral leukoplakia (OL) is a potentially malignant lesion of the oral mucosa in which there is an increased risk of malignant transformation compared to healthy mucosa. Today, many clinical, histopathological, and molecular factors are used as potential predictors of malignant transformation. Overall, conventional histopathological assessment remains the golden standard to determine malignancy in such cases. However, the assessment of dysplasia is subjective and for an accurate histopathological assessment experience is necessary. Understanding the process of carcinogenesis and the development of molecular biology has led to the discovery of new molecular biomarkers such as Ki67 and CD44 that could help in the early detection of tumors and their treatment. AIM OF THE RESEARCH: The aim of the research to immunohistochemically determine the presence of CD44 and Ki67 in OL and to compare the obtained data with the presence of CD44 and Ki67 in the oral squamous cell carcinoma (OSCC) and healthy oral mucosa. METHODS: 30 samples of oral mucosa diagnosed with OL, 30 samples of oral mucosa diagnosed with OSCC and 20 samples of oral mucosa without pathohistological changes analyzed. Sections of paraffin blocks and primary monoclonal antibodies to Ki67 (MO A-HU Ki67, clone MIB-1, 1: 150, DAKO) and to CD44 (MO A-HU CD44, clone DF 1485, 1:50, DAKO) used for immunohistochemical analysis. Immunohistochemical analysis for antibodies performed using the LSAB method as a visualization system on a Dako TechMateTM Horizon (Dako, Copenhagen, Denmark) automated machine for immunohistochemical staining. RESULTS: In the group diagnosed with OSCC, significantly more men compared to the OL groups and healthy oral mucosa were detected. The OSCC group was the oldest with a median age of 66.5 (IQR 52.2–72.0) years. A significant difference was noticed considering the presence of inflammation between the OL and OSCC group in regard to healthy mucosa, while no difference between the OL and OSCC group were observed. The inflammatory infiltrate described on hemalaun eosin (HE) in the stroma correlated with the presence of Ki67 in the inflammatory infiltrate in the stroma. Significant difference between the examined groups in relation to the presence of CD44 in the epithelium as well as in relation to the presence of Ki67 in the epithelium were observed. A statistically significant difference between the examined groups in relation to the CD44 in inflammatory infiltrate was observed, while a significant difference in terms of Ki67 in inflammatory infiltrate between OSCC and OL and OSCC and healthy mucosa, but not between OL and healthy mucosa were detected. A positive correlation between HE and Ki67 in the inflammatory infiltrate in the OL group were observed. Significant and positive correlations between HE inflammatory infiltrate and CD44 both in the epithelium and in the inflammatory infiltrate of the same group were observed. No significant correlation between HE inflammation and the examined molecular markers in the OSCC group was observed. A significant positive correlation between CD44 in inflammatory infiltrate with CD44 and Ki67 in the epithelium was observed, but only in the OL group, whereas no significant connection for OSCC was observed. CONCLUSION: An increased immunohistochemical presence of CD44 and Ki67 markers in OL suggests the need for new more extensive studies that would provide clinicians additional options for monitoring and predicting the behavior of individual lesions.