Aim: The aim of this study was to determine the most effective non-invasive surgical therapy in the treatment of oral leukoplakia by means of high energy ablative lasers. In addition, the aim was to compare the efficacy of ablative lasers and to evaluate subjective and objective postoperative parameters (healing, postoperative pain, quality of life, recurrence), all for the purpose of identifying the optimal laser and precision settings of lasers for clinical use in order to achieve a successful treatment of oral leucoplakias. Previous treatment methods such as scalpel excision, topical or systemic administration of retinoids and some lasers in a smaller or larger number of cases lead to recurrence of leukoplakia. For this reason, there is a need for finding more effective methods of treating oral leukoplakia. Therefore, the purpose of this study was to determine the efficacy of high energy ablative lasers in the treatment of oral leukoplakia. Furthermore, the purpose was to compare and evaluate subjective and objective postoperative parameters for two different ablative lasers such as erbium, yttrium, aluminum, garnet (Er: YAG) and erbium, chromium doped with yttrium, scandium, gallium, and garnet laser (Er: Cr: YSGG). Materials and methods: The study involved 54 subjects, of whom 16 men and 38 women. By random selection, the subjects were classified into one of the two study groups. In the first group of patients, the leukoplakic lesion was removed by high energy ablation laser Er: YAG and patients in the second group were treated by use of high energy ablative Er, Cr: YSGG laser. At the very beginning, the size of the leukoplakic lesion was measured in millimeters. The criterion for laser efficacy estimate was the recurrence of leukoplakic lesion during the one-year and six-month follow-up period. For the statistical analysis of the data, the Fisher's exact test was used for comparing discrete characteristics and the multivariate variance analysis (MANOVA) with three classification variables for comparing continuous characteristics. The Pearson correlation coefficient was used as the correlation measure. The analysis was made using the SAS statistical package on the Windows platform. Values of less than 0.05 were considered significant (p <0.05). Results: The results showed that there was a statistically significant difference in localization of lesion occurrence between men and women. In men, lesions usually occur on the cheeks, whereas in women they occur in the retromolar area and the area of the soft palate. Men are more likely to recur than women. After first therapy, the lesions treated by laser Er: Cr: YSGG showed less recurrence than those treated with Er: YAG laser and subjects reported a lower level of postoperative pain and higher quality of life after the treatment with Er: Cr: YSGG laser. Conclusion: From the aforementioned results, we can conclude that the Er: Cr: YSGG laser is more efficient and more acceptable for the treatment of oral leukoplakia than the Er: YAG laser.