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Aims: We aimed to assess the eradication efficacy and factors that influencing it of high‐dose dual therapy (HDDT) in Gansu region, Northwest China. Methods: A total of 216 treatment‐naive patients with Helicobacter pylori infection were randomly assigned to two groups for the 14‐day eradication treatment: the HDDT group (amoxicillin 750 mg q.i.d. and esomeprazole 40 mg t.i.d.) and the amoxicillin and clarithromycin‐containing bismuth quadruple therapy group (ACBQT: esomeprazole 20 mg, bismuth potassium citrate 2 g, amoxicillin 1 g, and clarithromycin 500 mg; b.i.d.). The eradication rates, adverse effects and patient compliance of these two groups were compared. Eradication efficacy was determined by 13C urea breath test (13C UBT) 4–8 weeks after finishing treatment. Antibiotic resistance was determined by the Epsilometer testing (E‐test) method. Results: The eradication rates for the HDDT and ACBQT groups were 71.0% and 74.7% (P =.552) by per‐protocol analysis, and 65.7% and 68.5% (P =.664) by intention‐to‐treat analysis. The overall adverse event rates in the HDDT and ACBQT groups were 2.0% and 43.4% (P <.001), respectively. The resistance rates to amoxicillin, clarithromycin, tetracycline, levofloxacin and metronidazole were 15.2%, 42.0%, 5.4%, 35.7% and 83.0%, respectively. Amoxicillin resistance and delta over baseline (DOB) of 13C UBT ≥ 20 before treatment significantly reduced the eradication rate in 112 participants with H. pylori cultured. Conclusion: The HDDT as first‐line treatment for H. pylori was unsatisfactory in Gansu. Amoxicillin resistance and DOB of 13C UBT ≥ 20 before treatment were significantly correlated with H. pylori eradication failure. [ABSTRACT FROM AUTHOR]