In areas with high clarithromycin resistance, bismuth quadruple therapy (BQT) is recommended instead of clarithromycin triple therapy (CTT) as the first-line treatment for Helicobacter pylori eradication. Randomized clinical trials (RCTs) comparing BQT to CTT were identified through electronic and manual searches. A meta-analysis was performed to compare the efficacy and tolerability of these two regimens as first-line treatments for H. pylori infection. The effect of antibiotic resistance on treatment efficacy was also analyzed. Twelve RCTs were included. BQT achieved eradication in 77.6% of patients, whereas CTT achieved an eradication rate of 68.9% [risk difference (RD) = 0.06, 95% CI: -0.01/0.13]. A high heterogeneity among the trials was found (χ2 = 50.16, p < 0.00001; I2 = 78%). In the subgroup analysis for treatment duration, the 10-day BQT was more effective than the 7-day CTT (RD = 0.25, 95% CI: 0.18/0.32), whereas no differences were observed between CTT and BQT given for 7 or 10 days. There were no statistical differences in side effects and compliance between both therapies (RD = 0.92, 95% CI: 0.76/1.12, and RD = -0.03, 95% CI: -0.05/0.00, respectively). The effect of antibiotic resistance on eradication rates was reported in 4 of the 12 RCTs. Clarithromycin resistance significantly affected the efficacy of CTT (RD = 0.75, 95% CI: 0.63/0.87), whereas BQT efficacy was not affected by metronidazole resistance (RD = 0.09, 95% CI: -0.06/0.25). The 10-day BQT was more effective than the 7-day CTT as a first-line therapy for H. pylori infection, whereas BQT and CTT for 7 or 10 days yielded similar eradication rates. Compliance and side effect rates were similar for both therapies. BQT overcomes clarithromycin resistance and its efficacy is not affected by metronidazole resistance.