Objective To investigate the efficacy and safety of potassium-competitive acid blocker vonoprazan in the treatment of Helicobacter pylori infection. Methods A total of 60 patients with Helicobacter pylori infection in our hospital from May 2020 to Dec. 2021 were selected and treated with a 4-drug combination regimen based on vonoprazan (vonoprazan treatment group). The treatment regimen was vonoprazan fumarate tablets 20 mg orally in the morning and evening, colloidal bismuth pectin capsules 150 mg orally 3 times a day, amoxicillin capsules 1.0 g orally in the morning and evening, and clarithromycin tablets 500 mg orally in the morning and evening, for 2 weeks. A retrospective paired study was conducted to select 60 patients with Helicobacter pylori infection treated with a 4-drug combination regimen based on proton pump inhibitor lansoprazole (lansoprazole treatment group) during the same period. The treatment regimen was lansoprazole enteric-coated tablets 30 mg orally in the morning and evening, colloidal bismuth pectin capsules 150 mg orally 3 times a day, amoxicillin capsules 1.0 g orally in the morning and evening, and clarithromycin tablets 500 mg orally in the morning and evening, for 2 weeks. The Helicobacter pylori eradication, medication compliance and adverse reactions (nausea, vomiting, abdominal pain, diarrhea, rash, etc.) of the 2 groups were statistically analyzed, and all patients were included for intention to treat (ITT) analysis. The patients with poor compliance and lost to follow-up were excluded for per-protocol (PP) analysis. Results Of the 120 patients, 5 were lost to follow-up, including 4 in the lansoprazole treatment group and 1 in the vonoprazan treatment group. The medication compliance of the lansoprazole treatment group and vonoprazan treatment group were 94.6% (53/56) and 96.6% (57/59), respectively, with no significant difference (P＞0.05). According to the analyses of ITT and PP, the eradication rates of Helicobacter pylori in the vonoprazan group were 93.3% (56/60) and 98.2% (56/57), respectively, which were significantly higher than those in the lansoprazole group (76.7% ［46/60］ and 86.8% ［46/53］) (both P＜0.05). There were 1 case of decreased appetite and 1 case of diarrhea during the medication process in the vonoprazan treatment group, and 2 cases of nausea and 1 case of abdominal discomfort in the lansoprazole treatment group. There was no significant difference in the incidence of adverse reactions between the 2 groups (3.33% ［2/60］ vs 5.00% ［3/60］, P＞0.05). Conclusion Four-drug combination regimen based on vonoprazan is more effective in the treatment of Helicobacter pylori infection compared with 4-drug combination regimen based on lansoprazole, and the safety and medication compliance of the 2 regimens are similar.