Background/Aims: Both proton pump inhibitor (PPI) and histamine-2-receptor antagonist (H2RA) are considered to be effective for the treatment of iatrogenic gastric ulcer after endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD). We aimed to systematically evaluate the evidence comparing PPI and H2RA for iatrogenic ulcer. Methods: Data from PubMed, Cochrane Library and Google Scholar were searched to identify eligible randomized trials. Outcome measures were delayed bleeding, epigastric pain and ulcer healing. Results: Six full-text studies were identified including a total of 522 patients. Pooled data suggested a significantly lower bleeding rate in the PPI group than in the H2RA group (odds ratio (OR) 0.49, 95% confidence interval (CI) 0.25-0.95). Subgroup analysis showed PPI was more effective in the prevention of bleeding than H2RA for ESD-induced ulcer (OR 0.41, 95% CI 0.20-0.85) and 8-week duration of medication (OR 0.36, 95% CI 0.17-0.76). There were no differences in the incidence of epigastric pain (OR 0.90, 95% CI 0.53-1.51) and ulcer healing rate after endoscopic therapies between both groups. Conclusion: This meta-analysis shows PPI is superior to H2RA for the prevention of delayed bleeding without different effectiveness in the reduction of epigastric pain and in the promotion of ulcer healing after EMR or ESD.