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Vonoprazan, a novel potassium-competitive acid blocking agent, is used in the management of gastroesophageal reflux disease (GERD). We aim to perform a systematic review and meta-analysis for the comparison of the effects of vonoprazan and proton pump inhibitors (PPIs) in GERD in randomized controlled trials (RCTs).A systematic and comprehensive search will be performed using MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), Google Scholar, and clinical trial registries, for studies published up to September 2018. Only randomized clinical trials will be included. Primary outcomes of symptoms and esophageal erosion improvement in the intention-to-treat analysis, and secondary outcomes of symptoms and esophageal erosion improvement rate in the per protocol analysis, the comparative efficacy in terms of healing rate of esophageal erosion on endoscopy, the comparative efficacy in terms of improvement of esophageal impedance-pH study, adverse events, long-term safety, and the comparative efficacy in terms of CYP2C19 metabolite levels will be studied. The quality of included studies will be assessed using the modified risk of bias tool. Heterogeneity of estimates across studies as well as publication bias will be assessed. This systematic review and meta-analysis will be performed according to the protocol recommended by the Cochrane Collaboration and reported according to the preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines. All statistical analyses will be conducted using Stata SE version 15.0.The results of this systematic review and meta-analysis will be published in a peer-reviewed journal.To our knowledge, this systematic review and meta-analysis will be the first to evaluate existing research comparing Vonoprazan and PPIs in GERD. Our study will provide information about the effect of vonoprazan and PPIs in GERD in RCTs. The review will benefit patients, healthcare providers, and policymakers.