(1) Background: Whether standard bismuth quadruple therapy (BQT) is superior to concomitant therapy for the first-line treatment ofHelicobacter (H.) pyloriinfection is unclear. The aim of this systematic review and meta-analysis was to compare the efficacy of standard BQT versus concomitant therapy forH. pylorieradication in subjects naïve to treatment. (2) Methods: Online databases were searched for randomized controlled trials. We pooled risk ratio (RR) of individual studies for dichotomous outcomes using a random-effect model. (3) Results: Six studies with 1810 adults were included. Overall intention-to-treat (ITT) eradication rate was 87.4% with BQT and 85.2% with concomitant therapy (RR 1.01, 95%CI:0.94–1.07). Subgroup analysis of five Asian studies showed a small but significant superiority of BQT over concomitant therapy (87.5% vs. 84.5%; RR 1.04, 95%CI:1.01–1.08). Pooling four studies at low risk of bias yielded a similar result (88.2% vs. 84.5%; RR 1.05, 95%CI:1.01–1.09). There was no difference between the regimens in the frequency of adverse events (RR = 0.97, 95%CI:0.79–1.2). (4) Conclusions: The efficacy of BQT seems to be similar to concomitant therapy, with similar side effect profile. However, BQT showed a small but significant benefit over concomitant therapy in Asian populations and in studies at low risk of bias.