A proton pump inhibitor (PPI) plus two antibiotics (amoxicillin and either clarithromycin or metronidazole) are recommended for treatment of acid-related disorders with Helicobacter pylori (H. pylori) infection. The aim of this pharmacogenetic study was to evaluate the efficacy of triple therapy with PPIs on eradication of H. pylori infection in relation to cytochrome P450 2C19 (CYP2C19) and P-glycoprotein (MDR1) gene polymorphisms. The retrospective study involved 70 Polish Caucasian patients with H. pylori infection, diagnosed and treated with one of the two different triple therapy regimens [omeprazole, amoxicillin, and clarithromycin (OAC) or pantoprazole, amoxicillin, and metronidazole (PAM)]. Using genomic DNA, CYP2C19 (*2 and *3) and C3435T MDR1 alleles were determined by means of polymerase chain reaction-restriction fragment length polymorphism assays. A significantly higher prevalence (P<0.05) of heterozygous extensive metabolizers (hetEM) with CYP2C19*1/*2 genotype (32.4% versus 8.3%) and homozygous with 3435TT MDR1 genotype (38.2% versus 13.9%) was found in patients cured after the first cycle of triple therapy than in patients with failure of eradication after the first cycle. CYP2C19*1/*2 and 3435TT MDR1 genotypes as well as PAM regimen of treatment were also predictive of successful eradication of H. pylori infection after the first cycle of triple therapy at univariate/multivariate logistic regression analysis. This pharmacogenetic study on the influence of different CYP2C19 and C3435T MDR1 genotypes on H. pylori eradication suggests that CYP2C19 and MDR1 polymorphisms may be independent predictable determinants of the efficacy of triple therapy including PPI. The PAM regimen of treatment seems to be more effective after the first cycle of the therapy than the OAC regimen.