We conducted a systematic review of the literature to evaluate treatment of oral leukoplakia with the carbon dioxide (CO2) laser. A comprehensive search of studies published between 1981 and 2015 and listed in the PubMed (National Library of Medicine, NCBI) database yielded 378 articles which were screened in detail. Rele- vant studies were selected according to predetermined inclusion and exclusion criteria. A total of 33 articles met the final inclusion criteria and were analysed in detail in accordance with the PRISMA-P statement. These full-text papers were classified as synopses (n 1⁄4 7), recurrence and malignant trans- formation studies (n 1⁄4 17), comparative studies between CO2 laser and cold knife surgery (n 1⁄4 3) and studies evaluating the efficacy of CO2, Nd:YAG and KTP lasers. According to the literature the CO2 laser is the workhorse of oral leukoplakia treatment due to its effectiveness and low associated morbidity. However, randomized clinical trials are needed to compare CO2 laser with other lasers. The results of our systematic review showed that there is no consensus regarding the factors involved in higher recurrence and malignization rates, so further studies are needed.