Objective · To explore the clinical efficacy of CO2 laser combined with photodynamic therapy (PDT) in the treatment of oral leukoplakia (OL). Methods · A total of 21 OL patients in Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine from June 2018 to June 2019 were recruited. They were randomly divided into experimental group (11 cases, treated with CO2 laser combined with PDT) and control group (10 cases, treated with CO2 laser). The adverse effects during the 1st week, the clinical efficacy at the 1st month and the recurrence at the 3rd and 6th months after treatment were recorded. The differences of the above indexes between the two groups were statistically analyzed. Results · At the 1st month after treatment, the significant efficiency of the experimental group and the control group was 100% and 80%, respectively, while the total treatment efficiency were 100% and 90%, respectively. There was no significant difference between the two groups. During the 1st week post-treatment, the patients experienced varying degrees of pain, edema and (or) erosion, and there was no significant difference between the two groups. At the 3rd month after treatment, the recurrence rate of the experimental group and the control group was 0 and 10%, respectively, with no statistical difference; at the 6th month after the treatment, the recurrence rate of the experimental group was significantly lower than that of the control group (P=0.038). Conclusion · Both CO2 laser combined with PDT and single CO2 laser have significant curative effect and no serious adverse effect on the treatment of OL, and the combination therapy can significantly reduce the rate of recurrence.