Helicobacter pylori infection remains a major public health concern and an important risk factor for peptic ulcer disease and gastric cancer. Although proton pump inhibitor (PPI)–based triple therapy has been the standard first-line treatment, eradication rates have declined due to antibiotic resistance and variable acid suppression. Vonoprazan, a potassium-competitive acid blocker (P-CAB), provides more potent and sustained acid inhibition; however, real-world data from Latin American populations are limited. To compare the effectiveness and safety of vonoprazan-based versus esomeprazole-based triple therapy for first-line Helicobacter pylori eradication in Brazil. A multicenter retrospective cohort study was conducted including 200 adult patients treated in three Brazilian tertiary centers between 2020 and 2023. Patients received 14-day triple therapy with either esomeprazole 40 mg twice daily or vonoprazan 20 mg twice daily, combined with amoxicillin and clarithromycin. H. pylori eradication confirmed by histology eight weeks after treatment was the primary outcome. Secondary outcomes included retreatment rates, adverse events, and treatment adherence. Multivariable logistic regression was used to adjust for potential confounders. Eradication rates were significantly higher in the vonoprazan group compared with the esomeprazole group (94.0% vs. 68.0%, p<0.001), with lower retreatment rates (6.0% vs. 32.0%, p<0.001). After adjustment for age and sex, vonoprazan-based therapy remained independently associated with eradication success (adjusted OR 7.24; 95%CI 3.12–16.81). Adverse event rates were similar between groups, with no severe events reported. In this multicenter real-world cohort, vonoprazan-based triple therapy was associated with significantly higher H. pylori eradication rates compared with esomeprazole-based therapy in Brazilian patients.