Objective To explore the efficacy of Vonoprazan based quadruple therapy in refractory Helicobacter pylori infection.Methods A total of 92 refractory Helicobacter pylori(Hp)positive patients who failed to cure with standard quadruple therapy in the Department of Gastroenterology,Nantong Haimen People's Hospital from January to December 2021 were selected as the study objects and they were divided into observation group (47 cases) and control group (45 cases) using stratified randomization.Observation group were treated with Vonoprazan,Amoxicillin,Levofloxacin,Bismuth Potassium Citrate,and control group were treated with Esomeprazole,Amoxicillin,Levofloxacin,Bismuth Potassium Citrate.The treatment course was 14 days in two groups.The 13C-urea breath was retested,and the eradication rate of Helicobacter pylori,improvement of digestive symptoms and incidence of adverse reactions were compared of the two groups after 4 weeks of withdrawal.Results A total of 85 patients (44 cases were in observation group and 41 cases were in control group)completed the experiment.According to the intention-to-treat (ITT),the Hp eradication rates were 87.2%in observation group and 57.8%in control group.According to the per-protocol (PP),the Hp eradication rates were 93.2%in observation group and 63.4%in control group.The Hp eradication rate in the observation group was higher than that in the control group,and the difference was statistically significant (P＜0.05).The gastrointestinal symptom scores of the two groups after successful Hp sterilization were lower than those before treatment in the same group,and the differences were statistically significant(P＜0.05).There was no statistically significant difference in the incidence of adverse drug reactions between the two groups(P＞0.05).Conclusion Vonoprazan based quadruple therapy has better curative effect on eradication of refractory Helicobacter pylori infection,obviously relieve the symptom of digestive tract and has no severe adverse reactions.