Objective To prospectively compare the efficacy of omeprazole and esomeprazole on H. pylori eradication related to cytochrome P450 (CYP) 2C19 polymorphism in Chinese Han poputafion. Methods A total of 240 patients with peptic ulcer were randomly assigned to receive either EAC (amoxicillin, clarithromyein and esomeprazole) treatment or OAC (amoxicillin, clarithromycin and orneprazole) treatment for one week with 120 each. Then, the patients were sustained treated with esomeprazol or omeprazole for 3 weeks. The endoscopic evaluation was performed 2 weeks after treatment. At the end of the treatment, a carbon-13 (13C) urea breath test (13C-UBT) was performed to determine H. pylori status. Polymerase chain reaction and restriction fragment length polymorphism were used to detect CYP2C19 genotypes including extensive metabolizer (EM), poor metabolizer (PM), homozygous (homEM) and hetEM. Results Two hundred and twenty five of 240 patients completed the study. H. pylori eradication was 79.2% with OAC regimen and 88.3% with EAC regimen by intention to-treat (ITT) analyses without difference (P>0.05). Whereas H. pylori eradication was 87.20/00 with OAC regimen and 91.4% with EAC regimen by per-protocol (PP) analyses without difference (P>0. 05). However, both ITT and PP analysis showed that there was significant difference in H. pylori eradication between EAC regimen (91.9% and 97.1%) and OAC regimen (71.8% and 77.8%) in patients with homEM genotype (P= 0.037 and P=0.028). Two weeks after treatment, the percentage of ulcer healing was 79.2% or 81.9% in EAC group and 69.2% or 76.1% in OAC group by ITT or PP analysis, respectively (P> 0.05). Low side effects were noted in EAC or OAC groups (3.3% vs. 7.5%,P>0.05). Conclusion The high eradication will be achieved by esomeprazole-based triple regimen which is superior to omeprazole-based triple regimen in treatment of patients with homEM genotype.