Background and Aims: Rebamipide is administered perorally to protect the gastric mucosa. We assessed the efficacy and safety of a novel rebamipide solution as a submucosal injection material for endoscopic submucosal dissection (ESD) using an in vivo porcine model. Methods: An endoscopist blinded to the test agents performed ESDs of hypothetical 30 mm lesions using a 2% rebamipide solution at 2 sites (rebamipide group) and a saline solution at 2 other sites (control group) in the stomachs of 8 pigs. The technical outcomes were compared between the 2 groups. The gastric ulcer stages were evaluated by endoscopy once weekly for 4 weeks after the ESD to determine the healing score (1-6). The pigs were killed at 1 week (n = 2), 2 weeks (n = 2), and 4 weeks (n = 4) after the ESD for pathologic evaluation of ESD-induced ulcers and scarring. Results: There were no significant differences in any of the technical outcomes between the 2 groups, and no adverse events related to the ESD in any of the animals. The healing score was significantly higher in the rebamipide group than in the control group at 2 weeks (P =.027), 3 weeks (P =.034), and 4 weeks (P =.012). In the histopathologic assessment, fibrosis was significantly less extensive in the rebamipide group than in the control group at 2 weeks (P =.02) and 4 weeks (P =.04). Conclusions: The rebamipide solution appeared to promote both the speed and quality of healing of ESD-induced ulcers by suppressing fibrosis.