Objective To compare different therapeutic regimens for treatment of Helicobacter pylori （Hp） infection combined with small intestinal bacterial overgrowth （SIBO）. Methods This study was a single?center， single?blind， 16?week randomized controlled trial to evaluate the efficacy of different therapeutic regimens for patients with Hp infection combined with SIBO. Patients who were co?positive for Hp and SIBO attending the outpatient and inpatient departments of the Department of Gastroenterology of the Sixth Medical Center of the PLA General Hospital from April 2022 to July 2023 were enrolled. The enrolled patients were randomly divided into 3 groups， A， B， and C. Different treatment regimens were applied to the three groups. The 13C?urea breath test and methane hydrogen breath test were reviewed respectively after 4 ~ 6 weeks of drug discontinuation， to compare the rate of co?conversion of Hp and SIBO， the degree of improvement of abdominal symptom scores， and the incidence of adverse reactions， such as diarrhea， constipation， and nausea in the three groups. Results There was no statistically significant difference in the Hp conversion rate among the three groups（P > 0.05）， and the SIBO conversion rate and co?conversion rate of group B were higher than that of group A（P < 0.05）， and the difference was not statistically significant compared with that of group C（P > 0.05）. The degree of improvement in GSRS score after treatment was higher in group B than in groups A and C （P = 0.015，P = 0.014）， and the overall adverse reactions in group B were lower than those in group A （P < 0.001）. The difference in overall adverse reactions between groups B and C was not statistically significant（P > 0.05）. The rate of SIBO conversion， the rate of co?conversion， and the degree of improvement in GSRS score after treatment were not statistically significant between group A and C（P > 0.05）， and the adverse reaction incidence was higher than that of group C （P = 0.004）. Conclusion Most patients with Hp infection combined with SIBO are accompanied by gastrointestinal discomforts such as acid reflux， heartburn， abdominal distension， constipation， and diarrhea， etc. HP treatment after removal of small intestinal bacteria can improve the rate of Hp and SIBO co?conversion， and effectively alleviate the abdominal symptoms and reduce the incidence of adverse reactions.