The aim of this study was to assess the efficacy of esomeprazole-based triple therapy compared with rabeprazole-based triple therapy according to CYP2C19 genotype and clarithromycin susceptibility status for first-line eradication therapy of Helicobacter pylori ( H. pylori ) in Japan. We enrolled 219 H. pylori -infected patients, and randomly allocated patients to the EAC group (esomeprazole 20 mg, clarithromycin 200 mg, amoxicillin 750 mg for one week, with all drugs given twice daily) or RAC group (rabeprazole 10 mg, clarithromycin 200 mg, amoxicillin 750 mg for one week, with all drugs given twice daily). The H. pylori eradication rate according to the PP analyses was 75.0% (95% CI: 65.2–82.8%) in the EAC group and 71.4% (95% CI: 61.4–79.1%) in the RAC group. There were no statistically significant differences. The eradication rates of the clarithromycin-resistant/-sensitive strains were, respectively, 45.0% (95% CI: 30.7–60.2%)/98.0% (95% CI: 88.7–100%) in the EAC group and 39.5% (95% CI: 25.6–55.3%)/93.5% (95% CI: 81.9–98.4%) in the RAC group. The eradication rate of the clarithromycin-sensitive strains was significantly higher than that of the resistant strains in both groups. In conclusion, EAC and RAC therapies show a comparable efficacy regardless of the CYP2C19 genotype and clarithromycin susceptibility status in Japan.