AIM To compare the effectiveness and safety of vonoprazan-based therapy with proton pump inhibitor(PPI)-based therapies to treat Helicobacter pylori(H. pylori).METHODS We retrospectively analysed data from first-line(vonoprazan or PPI with 200 mg clarithromycin and 750 mg amoxicillin twice daily for 7 d)(n = 1353) and second-line(vonoprazan or PPI with 250 mg metronidazole and 750 mg amoxicillin twice daily for 7 d)(n = 261) eradication treatments for H. pylori- positive patients with associated gastrointestinal diseases from April 2014 to December 2015 at Hattori Clinic, Japan. The primary endpoint was the eradication rate, which was assessed with a full analysis set. The secondary endpoints were adverse events and related factors.RESULTS After the first-line treatments, the eradication rates for vonoprazan, esomeprazol, rabeprazole, and lansoprazole were 87.9%(95%CI: 84.9%-90.5%), 71.6%(95%CI: 67.5%-75.5%), 62.9%(95%CI: 52.0%-72.9%), and 57.3%(95%CI: 50.4%-64.1%), respectively. The vonoprazan eradication rate was significantly higher than that of the PPIs(P < 0.01). Interestingly, smoking did not affect the H. pylori eradication rate in the vonoprazan group(P = 0.34), whereas it decreased the rates in the PPI groups(P = 0.013). The incidence of adverse events in the vonop-razan group was not different from the PPI group(P = 0.054), although the vonoprazan group exhibited a wider range of adverse events. Vonoprazan-based triple therapy was highly effective as a second-line treatment, with an eradication rate similar to that of PPI-based therapy.CONCLUSION Vonoprazan might be superior to PPIs in first-line H. pylori therapy, particularly for smokers. However, caution is required due to possible adverse events. AIM To compare the effectiveness and safety of vonoprazan-based therapy with proton pump inhibitor (PPI) -based therapies to treat Helicobacter pylori (H. pylori). METHODS We retrospectively analyzed data from first-line (vonoprazan or PPI with 200 mg clarithromycin and 750 mg amoxicillin twice daily for 7 d) (n = 1353) and second-line (vonoprazan or PPI with 250 mg metronidazole and 750 mg amoxicillin twice daily for 7 d) (n = 261) eradication treatments for H. pylori- positive patients with primary gastrointestinal diseases from April 2014 to December 2015 at Hattori Clinic, Japan. The primary endpoint was the eradication rate, which was assessed with a full analysis set. The secondary endpoints were adverse events and related factors. RESULTS After the first-line treatments , the eradication rates for vonoprazan, esomeprazol, rabeprazole, and lansoprazole were 87.9% (95% CI: 84.9% -90.5%), 71.6% (95% CI: 67.5% -75.5%), 62.9% (95% CI: 52.0 % -72.9%), and 57.3% (95% CI: 50.4% -64.1%), respectively. The v Interestingly, smoking did not affect the H. pylori eradication rate in the vonoprazan group (P = 0.34), it it decreased the rates in the PPI groups (P = 0.013). The incidence of adverse events in the vonop-razan group was not different from the PPI group (P = 0.054), although the vonoprazan group exhibited a wider range of adverse events. Vonoprazan-based triple therapy was highly effective as a second-line treatment, with an eradication rate similar to that of PPI-based therapy. CONCLUSION Vonoprazan might be superior to PPIs in first-line H. pylori therapy, particularly for smokers. However, caution is required due due to possible adverse events.