Background and objectives: There is inadequate data on the clinical outcomes of proton pump inhibitors in patients with post-endoscopic submucosal dissection (ESD) gastric ulcers (PESDGU). The clinical course of PESDGU is affected by various ESD methods, including the types of devices and endoscopists’ skills. No previous reports have compared the clinical outcomes of different proton pump inhibitors for PESDGU healing in patients who underwent the same ESD method using the same device by the same well-trained endoscopist. This study aims to compare the clinical outcome of esomeprazole vs. rabeprazole in PESDGU using the same ESD method and by the same endoscopist. Methods: Sixty patients with gastric tumors participated in this randomized clinical trial. Patients who underwent ESD using the Clutch Cutter (ESDCC) method by the same endoscopist were prospectively randomly assigned to esomeprazole 20 mg (EM) or rabeprazole 20 mg (RM) monotherapy groups. All patients received 20 mg omeprazole intravenously daily for the first 2 days post-ESDCC, followed by oral administration of EM or RM for 8 weeks. All patients remained hospitalized for 7 days postoperation to monitor any ESD-related complications. Esophagogastroduodenoscopy was performed 8 weeks post-ESD to evaluate the healing status of each artificial ulcer. Results: Of the 60 patients in this study, 30 each were assigned to the EMand RM groups. Eight patients from both groups did not complete the regimen and were excluded. Exactly 52 patients completed the study, with 27 and 25 in the EM and RM groups, respectively. There were no significant differences in the demographic characteristics of the two groups. There were no post-ESD perforations in either group. Post-ESD bleeding occurred in one patient in the RM group 5 days post-ESD. Scarring rates at the endpoint 8 weeks after ESD in the EM and RM groups were 96% and 76%, respectively. There were no significant differences between the two groups in the scarring stage (S1 or S2) at 8 weeks post-ESD. Conclusion: EM and RM have equivalent therapeutic effects on PESDGUs.