Objective To compare the efficacy and the risk of adverse effect of drug susceptibility test guided therapy and novel empirical quadruple therapy for Helicobacter (H.) pylori infection.Methods Literature retrieval was conducted by using major databases.Related papers published up to June 2015 were considered eligible if they were randomized control trials comparing different pharmacological formulations for H.pylori infection and used in a network Meta-analysis and a single rate Meta-analysis to evaluate the relative and absolute rates of H.pylori eradication and the risk of adverse effect.The Jadad score was used to evaluate the methodological quality.Funnel plot was constructed to evaluate the risk of publication bias.Begg's rank correlation test or Egger's regression intercept test was done for the asymmetry of funnel plot.Results Twenty randomized control trials for the treatment of 6 753 initial treated patients with H.pylori infection were included.Drug susceptibility test guided therapy was significantly superior to concomitant therapy,hybrid therapy,sequential therapy and bismuth quadruple therapy.The culture-based therapy had the highest likelihood of improving clinical efficacy,with lowest risk of adverse effect.Concomitant therapy had the highest probability of causing adverse effect despite its effectiveness.Hybrid therapy and bismuth quadruple therapy were associated with lower risk of adverse effect and higher effectiveness.Conclusion Drug susceptibility test guided therapy showed superiority to other 4 interventions for H.pylori eradication mentioned above.Hybrid therapy and bismuth quadruple therapy might be applied in the settings where the culture-based strategy is not available.