Background The decreasing efficacy of H. pylori eradication treatments over time makes the search for better regimens and adjuvant medications a priority. Aim To conduct a meta-analysis of studies comparing rabeprazole or esomeprazole with other proton pump inhibitors (PPI) or with each other in H. pylori eradication treatment. Methods Selection of Studies: Randomised clinical trials comparing esomeprazole or rabeprazole with first-generation PPIs (omeprazole-lansoprazole-pantoprazole) or with each other. Results The meta-analysis (35 studies, 5998 patients) showed higher eradication rates for esomeprazole than for first-generation PPIs: 82.3% vs. 77.6%; OR = 1.32(1.01-1.73); NNT = 21. Rabeprazole also showed better results than first-generation PPIs: 80.5% vs. 76.2%; OR = 1.21(1.02-1.42); NNT = 23. PPI dosage sub-analysis: only esomeprazole 40 mg b.d. improved results [83.5% esomeprazole vs. 72.4% first generation; OR = 2.27(1.07-4.82); NNT = 9]. Whereas rabeprazole 10 and 20 mg b.d. maintained results, esomeprazole 20 mg b.d. obtained lower efficacy. Esomeprazole vs. rabeprazole sub-analysis (five studies): no significant differences were found: 78.7% vs. 76.7%; OR = 0.90(0.70-1.17). CYP2C19 sub-analysis: Genotype did not significantly affect eradication either in first [OR = 1.76(0.99-3.12)] or new generation [OR = 1.19(0.73-1.95)] PPIs. However, sub-analysis considering only extensive metaboliser patients showed higher eradication with new-generation PPIs [OR = 1.37(1.02-1.84)]. Conclusions Esomeprazole and rabeprazole show better overall H. pylori eradication rates than first-generation PPIs. This clinical benefit is more pronounced in esomeprazole 40 mg b.d. regimens. In CYP2C19 extensive metabolisers, new-generation PPIs are more effective than first-generation PPIs for H. pylori eradication. However, a general recommendation of using new-generation PPIs in all scenarios remains unclear. © 2012 Blackwell Publishing Ltd.