This randomized controlled clinical trial was designed to evaluate the efficacy of single-session, non-thermal, carbon dioxide (CO(2)) laser irradiation in relieving the pain of minor recurrent aphthous stomatitis (miRAS) as a prototype of painful oral ulcers. Fifteen patients, each with two discrete aphthous ulcers, were included. One of the ulcers was randomly allocated to be treated with CO(2) laser (1 W of power in de-focused continuous mode) and the other one served as a placebo. Before laser irradiation, a layer of transparent, non-anesthetic gel was placed on both the laser lesions and the placebo lesions. The patients were requested to grade their pain on a visual analog scale up to 96 h post-operatively. The reduction in pain scores was significantly greater in the laser group than in the placebo group. The procedure itself was not painful, so anesthesia was not required. Powermetry revealed the CO(2) laser power to be 2-5 mW after passing through the gel, which caused no significant temperature rise or any visual effect of damage to the oral mucosa. Our results showed that a low-intensity, non-thermal, single-session of CO(2) laser irradiation reduced pain in miRAS immediately and dramatically, with no visible side effects.