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Recent treatment guidelines recommend two first-line therapies forHelicobacter pyloriinfection: proton pump inhibitor (PPI), bismuth, tetracycline, and metronidazole (quadruple therapy) or PPI, clarithromycin, and amoxicillin (triple therapy). We performed a systematic review and meta-analysis to compare the efficacy and tolerability of these regimens as first-line treatment ofH. pylori.A search of MEDLINE, EMBASE, Google Scholar, the Cochrane Central Register of Controlled Trials,ACP Journal Club, the Database of Abstracts of Reviews of Effectiveness, Cochrane Methodology Register, Health Technology Assessment Database, and abstracts from prominent gastrointestinal scientific meetings was carried out. Randomized controlled trials (RCTs) comparing bismuth quadruple therapy to clarithromycin triple therapy were selected for meta-analysis. Two independent reviewers extracted data, using standardized data forms. Meta-analysis was carried out with the metan command in Stata 10.1. Funnel plots and subgroup analyses were carried out.Nine RCTs (N=1,679) were included. Although dosing regimens of clarithromycin triple therapy were quite consistent between trials, dosing regimens varied considerably for bismuth quadruple therapy. Bismuth quadruple therapy achieved eradication in 78.3% of patients, whereas clarithromycin triple therapy achieved an eradication rate of 77.0% (risk ratio (RR)=1.002, 95% confidence interval (CI): 0.936–1.073). There was moderate heterogeneity and no evidence for significant publication bias. Subgroup analyses by study location, treatment duration, and study population did not account for the heterogeneity. There were no statistically significant differences in side effects yielded by quadruple vs. clarithromycin triple therapy (RR=1.04, 95% CI: 1.04–1.14).Quadruple and triple therapies yielded similar eradication rates as primary therapy forH. pyloriinfection. Both therapies yielded suboptimal eradication rates. Patient compliance and side effects are similar for quadruple and triple therapies.