Currently, although there are many randomized controlled trials comparing the effectiveness of proton pump inhibitors and H2-antihistamines in relation to peptic ulcer disease, meta-analytical studies on this topic are still limited and conclusions have not come to consensus. Therefore, a meta-analysis of randomized controlled trials evaluated by the Cochrane Collaboration tool is essential. From January 1st, 1985, to May 31st, 2022, the study was carried out on three databases: Pubmed, Cochrane, and Embase. Statistics are expressed as odds ratios, with confidence intervals of 95 %, and a random effects model is used. Results: Proton pump inhibitors increase the effectiveness of treatment more than H2-antihistamines. Specifically, on prevention subjects = 0.15 (95 % CI: 0.05-0.44), patients who are monitored for relapse rates without medication = 0.92 (95 % CI: 0.75-1.14), and with medication = 0.50 (95 % CI: 0.31-0.80). In conclusion, proton pump inhibitors are the first-line medicine for ulcer prevention and post-healing monitoring.