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This study evaluated the efficacy and tolerability of potassium-competitive acid blocker (P-CAB), a new class of gastric acid inhibitory agents, as first-lineH. pylorieradication treatment compared with 7-day proton pump inhibitor (PPI)-based triple therapy.We retrospectively reviewed the medical records of 661 consecutive patients who received first-lineH. pylorieradication treatment between January 2013 and October 2015. Patients who received 7-day P-CAB therapy (vonoprazan 20 mg+amoxicillin 750 mg+clarithromycin 200 mg twice/day;n=181) were compared with those who received 7-day PPI therapy (lansoprazole 30 mg/rabeprazole 20 mg+amoxicillin 750 mg+clarithromycin 200 mg twice/day;n=480) using propensity score matching analysis. The successful eradication and adverse event rates were compared between the two groups.The propensity score matching analysis yielded 175 matched pairs. Adjusted comparisons between the two groups showed a significantly higher eradication rate for the P-CAB than the PPI group in both intention-to-treat (89.1 vs. 70.9%;P<0.001) and per-protocol analyses (91.2 vs. 71.7%;P<0.001). There was no significant difference in the incidence of adverse events between the two therapies except skin rash. No patients discontinuedH. pylorieradication treatment because of adverse events.Seven-day P-CAB-based triple therapy was more effective than 7-day PPI-based triple therapy as a first-lineH. pylorieradication treatment. Seven-day P-CAB-based triple therapy was generally well-tolerated.