Risk factors for gastric cancer are receiving renewed attention in light of the recent positive association of Helicobacter pylori infection with gastric cancer. The effect of H.pylori on the balance between oxidants and antioxidants in the stomach is not well known. In this study, we investigated if exposure of gastric cells to H.pylori increases oxidant-associated gastric epithelial cell injury. A human gastric epithelial cell line (AGS) was grown on 96-well clusters, then exposed overnight to either live H.pylori (four cagA⁺ and four cagA^–) or broth culture supernatant from an isogenic H.pylori cagA⁺ strain with and without vacA activity. Incubation of AGS cells with cagA⁺ and cagA^–H.pylori strains before exposure to reactive oxygen species (ROS) reduced cell viability on average to 73.7% and 39.5% of controls, respectively. The percent viability of cells exposed to ROS after incubation with control broth, vacA^– broth and vacA⁺ broth was 97.7%, 70.5% and 63.5%, respectively. Experiments were then performed to evaluate the effects of H.pylori exposure on the activities of ROS-scavenging enzymes [catalase, glutathione peroxidase and superoxide dismutase (SOD)] and formation of 8-hydroxy-2-deoxyguanosine (8-OH-dG) adducts in AGS cells. Overnight exposure to cagA^– strains reduced catalase activity by 42%; in contrast, exposure to cagA⁺H.pylori strains increased catalase activity by 51%. Glutathione peroxidase activity increased with exposure to both cagA^– and cagA⁺ strains by 95% and 240%, respectively. Total SOD activity increased 156% after exposure to cagA⁺ strains and was marginally increased (52%) with exposure to cagA^– strains. CuZn-SOD protein levels, assayed by enzyme-linked immunosorbent assay, were not significantly altered by exposure to H.pylori strains; however, Mn-SOD concentrations were significantly increased (P < 0.02) after exposure to both cagA^– and cagA⁺H.pylori strains. Exposure of AGS cells to cagA⁺ and cagA^–H.pylori was associated with, on average, 44.5 and 99.0 8-OH-dG/10⁶ dG, respectively. The increase in catalase, glutathione peroxidase and SOD activity is associated with fewer 8-OH-dG DNA adducts and reduced susceptibility of AGS cells to lethal injury from ROS after exposure to cagA⁺H.pylori strains when compared with exposure to cagA^–H.pylori strains. Alteration in the activity of ROS-scavenging enzymes by the presence of H.pylori may in part be responsible for the increased risk of gastric cancer in persons infected with H.pylori.