Objective To compare proton pump inhibitors (PPI) and H2 receptor antagonists (H2RA) for both the prevention of bleeding and the healing of ulcer after endoscopic submucosal dissection (ESD), so as to provide best evidence for treating ESD-induced ulcer in clinic. Methods Databases including PubMed, CENTRAL, EMbase, ISI Web of Knowledge, VIP, CNKI, CBM and WanFang Data were searched from the date of their establishment to October 26, 2012 to collect the randomized controlled trials (RCTs) about comparison of PPI and H2RA on the prevention of bleeding and the healing of ulcer after ESD. Meanwhile the references of the included studies were also retrieved manually. According to the inclusion and exclusion criteria, literature selection, data extraction and quality assessment were performed by four reviewers independently, and meta-analysis was performed using RevMan 5.1 software. Results A total of 6 studies involving 616 patients were included finally. The results of meta-analysis showed that: for the prevention of ulcer bleeding after ESD, PPI preceded H2RA apparently (OR=0.51, 95%CI 0.29 to 0.89, P=0.02), especially when the treatment course was 8-week (OR=0.43, 95%CI 0.22 to 0.82, P=0.01); but among the merged, 8-week and 4-week groups, there were no significant differences between PPI and H2RA in the healing of ESD-induced ulcer (OR=0.85, 95%CI 0.39 to 1.86, P=0.69; OR=1.33, 95%CI 0.28 to 6.27, P=0.72; OR=0.75, 95%CI 0.31 to 1.79, P=0.52). Conclusion PPI is superior to H2RA for the prevention of ulcer bleeding induced by ESD, but there is no significant difference between them in the healing of ulcer, so PPI is recommended to prevent ESD-induced ulcer bleeding in clinic. Due to the limitation of quantity and quality of the included studies, the safety of PPI has to be further proved by conducting more high quality, large scale and multicenter RCTs.