BACKGROUND: Helicobacter pylori causes peptic ulcers and accounts for over 90% of gastric cancers; however, eradication rates have been declining due to antimicrobial resistance. Vonoprazan (VPZ), a potassium-competitive acid blocker, produces rapid and profound gastric acid suppression and has shown promising effects in the improvement of H. pylori eradication rates. The efficacy and safety of VPZ-based triple therapy as a first-line regimen for H. pylori eradication and its relationship with clarithromycin (CAM) susceptibility were evaluated. METHODS: From May 2015 to September 2017, H. pylori-infected patients who underwent esophagogastroduodenoscopy with CAM susceptibility testing were prospectively enrolled. Patients received a 7-day triple therapy regimen (VAC) of VPZ (20 mg), amoxicillin (750 mg), and CAM (200 mg) twice daily. Eradication rates, demographics, CAM susceptibility, and safety profiles were assessed. RESULTS: VAC was administered to 146 patients (median age: 63, range: 22-85 years) (60% of whom were females) who underwent CAM susceptibility testing, and 131 patients underwent C-urea breath testing to evaluate eradication success. The prevalence of CAM resistance was 34.2%. The overall eradication rates of VAC in per protocol (PP) and "intention to treat" (ITT) analyses were 90.8% (n = 131) and 81.5% (n = 146), respectively. In PP analysis for CAM susceptibility, the eradication rates of VAC were comparable between CAM-sensitive (91.6%, n = 83) and CAM-resistant (89.4%, n = 47) strains. The corresponding rates from the ITT analysis were 80.0% (n = 95) and 84.0% (n = 50), respectively. No adverse events requiring discontinuation of VAC were observed. CONCLUSIONS: CAM-resistant H. pylori was prevalent in one-third of patients in the Tokyo metropolitan area. VPZ-based triple therapy was highly effective and well-tolerated irrespective of CAM susceptibility. Therefore, it could be a valuable first-line treatment regimen for H. pylori infection.