WHAT IS KNOWN AND OBJECTIVE: The Helicobacter pylori (H. pylori) eradication rate of proton pump inhibitor (PPI)-based regimen remains decreasing. Vonoprazan (VPZ), a stronger and longer-lasting acid blocker, has been proposed to treatment of H. pylori infection. However, previous reviews did not have a pre-established study protocol and did not conduct a comprehensive search of the database, so the results obtained were not robust. We aimed to perform a meta-analysis to assess the effectiveness and safety of VPZ-based regimens for treatment of H. pylori infection in comparison with other regimens. METHODS: We conducted a systematic literature search on PubMed, Embase, Cochrane Library, Web of Science, ClinicalTrials and ChiCTR Register. Randomized clinical trials comparing VPZ-based regimens with similar eradication regimens without VPZ in the treatment of H. pylori infection were included. Eradication rate, compliance of the patients and side effects were specified as the primary outcomes. RevMan 5.4 software was used to analyze the RCTs and provide pooled risk ratio (RR) with 95% confidence intervals (CI). Systematic searches, study selection, data extraction, risk of bias assessment and statistical analysis were performed by two independent researchers according to the predesigned criteria on the PROSPERO. RESULTS AND DISCUSSION: A total of 8 RCTs with 2012 patients qualified for evaluation. The results showed that the eradication rate of VPZ-containing regimens was significantly superior to PPI-containing regimens for both intention-to-treat (RR, 1.14; 95% CI: 1.06-1.23; p = 0.0006) and per-protocol analyses (RR, 1.12; 95% CI: 1.04-1.20; p = 0.003). Subgroup analysis based on treatment regimens, eradication experience and clarithromycin resistance, as well as sensitivity analysis further confirmed this finding. In addition, there was no significant difference in compliance (RR, 1.02; 95% CI: 0.98-0.1.05; p = 0.35) and the frequency of adverse events (RR, 0.84; 95% CI: 0.70-1.00; p = 0.05) between the regimens. WHAT IS NEW AND CONCLUSION: Compared with PPI-based regimens, the VPZ-containing regimens showed a comparable or even superior eradication rate of H. pylori in terms of overall comparison and comparison of different treatment regimens, eradication experience and clarithromycin resistance. In addition, VPZ-based regimens have better tolerability and fewer adverse events. More future studies are needed to evaluate the impact of some differences in patient characteristics. TRIAL REGISTRATION: PROSPERO CRD42021229598.