Background <p>Both traditional proton pump inhibitors and the novel potassium-competitive acid blocker vonoprazan, when combined with high-dose amoxicillin in dual therapy, have shown promise for <i>Helicobacter pylori</i> (<i>H. pylori</i>) eradication. However, high-quality evidence directly comparing their efficacy and safety remains limited. This study aimed to compare the clinical efficacy and safety of rabeprazole-amoxicillin dual therapy versus vonoprazan-amoxicillin dual therapy for <i>H. pylori</i> eradication.</p> Methods <p>From April 1, 2024, to February 28, 2025, 318 <i>H. pylori</i>-positive patients were enrolled and randomly assigned in a 1:1 ratio to two treatment groups: the Rabeprazole Group (rabeprazole 20&#xa0;mg twice daily; amoxicillin 1000&#xa0;mg three times daily) and the Vonoprazan Group (vonoprazan 20&#xa0;mg twice daily; amoxicillin 1000&#xa0;mg three times daily). Both groups received a 14-day treatment course. A ¹³C-urea breath test was performed at least four weeks after treatment completion. <i>H. pylori</i> eradication rates, incidence of adverse events during treatment, and medication adherence were compared between the groups.</p> Results <p>In the intention-to-treat analysis, the eradication rates were 75.5% (95% CI: 68.8%-82.2%) in the Rabeprazole Group and 83.0% (95% CI: 77.2%-88.9%) in the Vonoprazan Group, with no statistically significant difference (<i>P</i> = 0.097). In the modified intention-to-treat analysis, the rates were 78.4% (95% CI: 71.9%-84.9%) and 88.6% (95% CI: 83.5%-93.7%), respectively, showing a significant difference (<i>P</i> = 0.018). In the per-protocol analysis, the rates were 79.7% (95% CI: 73.1%-86.3%) and 90.1% (95% CI: 85.1%-95.0%), respectively, also showing a significant difference (<i>P</i> = 0.015). The incidence of adverse events was low in both groups (10.5% vs. 12.8%, <i>P</i> = 0.533). Medication adherence did not differ significantly between the groups (<i>P</i> = 0.648). Manual labor occupation was identified as a risk factor for eradication failure (adjusted OR = 2.153, 95% CI: 1.067 to 4.346, <i>P</i> = 0.032).</p> Conclusion <p>Vonoprazan-amoxicillin dual therapy achieves satisfactory outcomes for <i>H. pylori</i> eradication, with a significantly higher eradication rate than the traditional rabeprazole-amoxicillin dual regimen. As a novel acid suppressant, vonoprazan demonstrates significant clinical advantages and broad application potential in dual-therapy regimens for <i>H. pylori</i> eradication.</p> Clinical trial registration <p><a href="https://www.medicalresearch.org.cn/">https://www.medicalresearch.org.cn/</a>, identifier ChiCTR2400082319. Registered on March 5, 2024.</p>