Objective: Compared 14-day high-dose esomeprazole-based quadruple therapy (14-HEQT), 14-day standard-dose esomeprazole-based quadruple therapy (14-EQT), and 14-day standard-dose quadruple therapy efficacy of non-esomeprazole-based quadruple therapy (14-NEQT) for eradication of Helicobacter pylori (Hp), and looking for risk factors associated with eradication failure. Methods: A retrospective analysis of 312 patients diagnosed with Hp infection. Regimens of quadruple therapy with 14-HEQT or 14-EQT or 14-NEQT were received between June 2019 and March 2022, and the effect of Hp eradication was detected by 13C-urea breath test. Results: The eradication rates of 14-HEQT group, 14-EQT group, and 14-NEQT group were 80.88% (55/68), 66.00% (66/100), and 63.89% (92/144), respectively, and the eradication rate of Hp in 14-HEQT group was significantly higher than that in 14-EQT group (P=0.0373) and 14-NEQT group (P=0.0162). The incidence of adverse events in the 14-HEQT group was 7.35%, the incidence of adverse events in the 14-EQT group was 5.00%, and the incidence of adverse events in the 14-NEQT group was 5.56%. There was no statistical significance in the incidence of adverse reactions among the 3 groups (P>0.05). Multivariate analysis showed that both gender and comorbidity with diabetes were associated with failure of Hp eradication therapy (P=0.0079, P=0.0098). Conclusion: High-dose quadruple therapy based on esomeprazole can significantly improve the eradication rate of Hp with low incidence of adverse reactions, which is worthy of clinical application.