Objective To evaluate the efficacy and safety of high-dose dual therapy (HDDT) in the treatment of Helicobacter pylori (HP) infection. Methods The clinical data of patients with HP infection who were treated in Suining Central Hospital between June 2020 and August 2021 were retrospectively collected. They were divided into HDDT group and bismuth-containing quadruple therapy (BQT) group according to the treatment regimen. The efficacy and adverse reactions of the two treatment regimens were observed. Results A total of 520 patients were included. Among them, there were 284 cases in the HDDT group and 236 cases in the BQT group. By propensity score matching, 223 pairs of patients were successfully matched. The eradication rates of HDDT and BQT were 74.4% and 77.1%, respectively (χ2=0.440, P=0.507), and the incidence of adverse reactions were 9.9% and 16.6%, respectively (χ2=4.395, P=0.036). Conclusion The efficacy of HDDT and BQT in the treatment of HP infection is comparable, but the former has fewer adverse reactions.