The aim of the study was to prove the rationale for antiviral therapy combined with surgical procedures for treatment of severe oral leukoplakia. Complex clinical and laboratory evaluation and treatment was performed in 56 patients divided in 2 groups. Control group was presented by 13 patients receiving dental treatment, local and systemic keratoplastic formulations. Main group involved 43 patients in which conventional treatment protocol was completed by antiviral therapy and surgical procedures. Leukoplakia diagnosis was based on clinical findings, histological and immunohistochemical studies as well as optic coherent tomography data. The obtained results evidently prove the necessity for including antiviral therapy and surgical procedures in treatment scheme of severe oral leukoplakia