This study assessed a novel approach using defocused carbon dioxide (CO2) laser irradiation on the gastric mucosal surface to reduce gastric acid output. Ninety-six Sprague-Dawley rats were randomised to three groups: control, surgical highly selective vagotomy (surgical-HSV), and gastric mucosal irradiation (laser-M). Cysteamine-induced peptic ulceration was studied, including ulcer index (product of the total number of ulcers by the sum of the ulcer length), at 4 weeks and 20 weeks. The mean ulcer index in the surgical-HSV group was significantly reduced compared with controls at 4 weeks and at 20 weeks. The mean ulcer index in the laser-M group was significantly reduced compared with controls at 4 weeks but not at 20 weeks. Histologic analysis did not reveal any mucosal changes in parietal cell mass at 4 weeks and at 20 weeks. The results show a transient antiulcer effect produced by the gastric mucosal irradiation seen at 4 weeks and abolished by 20 weeks. This data supports the feasibility of endoscopic management of peptic ulcer disease.