Background and aims:Regarding the laser energy delivery with non-tissue alteration when irradiating CO2 laser to the transparent gel, it was worth exploring the clinical efficacy of pain relief on oral ulceration using aphthous stomatitis as a model for painful oral ulcer. The aims of this study were to compare pain scores, daily activity-disturbance scores and sizes of the ulcers between the laser group and the placebo group. Subjects and methods:The double blind-randomized-placebo-controlled trial was conducted in 14 patients with aphthous ulcers. The subjects were allocated into 2 groups; namely, the laser group and the placebo group. The two baselines were measured on the day before and the treatment day. Then the lesions were covered with the transparent gel and irradiated by either 2 W defocused CO2 laser for 5 seconds or the sham laser. The outcomes were collected immediately, on day 1, 3, 5 and 7 after treatment. Results: The means of pain and daily activity-disturbance scores of the laser group were lesser than the placebo group in every episode. A statistically significant difference between the groups was found only the pain score on day 3 after treatment (P-value<0.001, 95% CI of the difference = 8.8 to 19.20 mm). There were no statistically significant differences in the daily activity-disturbance scores and the sizes of the ulcers between the groups (P value > 0.05). Conclusion:The CO2 laser therapy used in this clinical study was able to relieve pain from aphthous stomatitis compared with the placebo on the day 3 after treatment.