The aim of our study was to investigate the impact of interleukin (IL)-6 190C/T, IL-6 174G/C, IL-6 572G/C, tumor necrosis factor-alpha (TNF-α) 308G/A, and angiotensin-converting enzyme (ACE) I/D gene polymorphisms on Helicobacter pylori (H. pylori) infection in children.A cross-sectional study was performed on 126 children (57 children with H. pylori infection and 69 children without H. pylori infection) aged between 3 and 18 years presenting to a Pediatrics Tertiary Hospital from Romania. Children were assessed clinically, endoscopically, histopathologically, and genetically.In our study, we found that the presence of the CT and CT+TT genotypes of IL-6 190C/T (P < .002 and P = .04), allele G of IL-6 572 G/C polymorphism (P = .01), genotypes GA and AA of TNF-α 308 G/A polymorphism (P = .04, P = .01), and genotype II of ACE I/D polymorphism (P = .02) were associated with H. pylori infection, while the CC genotype of IL-6 174G/C polymorphism was scarcely encountered in children with H. pylori infection [P = .02, odds ratio (OR) = 0.06; 95% confidence interval (95% CI): 0.003-0.128]. Taking under consideration the 4 variant genotypes (IL-6 572G/C, IL-6 190C/T, TNF-α 308G/A, and ACE I/D), we noticed a 2 times higher incidence of H. pylori infection (OR = 6.34; 95% CI: 2.15-25.8).We may consider that the IL-6 190C/T, IL-6 174G/C, IL-6 572G/C, TNF-α 308G/A, and ACE I/D gene polymorphisms may increase the children's susceptibility for acquiring H. pylori infection; therefore, they may contribute to the pathogenesis of H. pylori gastritis.