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Background Current guidelines recommend bismuth-containing quadruple therapy (BQT) and quinolone-containing therapy after failure of first-line Helicobacter pylori eradication therapy. However, the optimum regimen of second-line eradication therapy remains elusive. We conducted a network meta-analysis to compare the relative efficacy of 16 second-line H. pylori eradication regimens. Methods Three major bibliographic databases were reviewed to enrol relevant randomised controlled trials between January 2000 and September 2018. Network meta-analysis was conducted by STATA software and we performed subgroup analysis in countries with high clarithromycin resistance and high levofloxacin resistance, and in patients with documented failure of first-line triple therapy. Results Fifty-four studies totalling 8752 participants who received 16 regimens were eligible for analysis. Compared with a 7-day BQT, use of probiotic add-on therapy during, before, and after second-line antibiotic regimens, quinolone-based sequential therapy for 10–14 days, quinolone-based bismuth quadruple therapy for 10–14 days, bismuth quadruple therapy for 10–14 days, and quinolone-based triple therapy for 10–14 days were significantly superior to the other regimens. Subgroup analysis of countries with high clarithromycin resistance and high levofloxacin resistance revealed that the ranking of second-line eradication regimens was distributed similarly in each group, as well as in patients with failure of first-line triple therapy. Conclusion We conducted a detailed comparison of second-line H. pylori regimens according to different antibiotic resistance rates and the results suggest alternative treatment choices with potential benefits beyond those that could be achieved using salvage therapies recommended by guidelines.