Olive oil, the main fat component of the Mediterranean diet, has been found to be protective against oxidative stress and could be beneficial in inflammatory and gastrointestinal disorders. First-pressed, extra-virgin olive oil (EVOO) has appreciable amounts of powerful antioxidants such as polyphenolic compounds that prevent its autoxidation and are responsible for its high stability. The aim of the present study was to determine whether diets supplemented with EVOO could reduce the severity of indomethacin-induced gastric oxidative damage and also to study changes in the activities of certain oxidative stress-related enzymes such as xanthine oxidase, myeloperoxidase as a marker of neutrophil infiltration, and the antioxidant enzyme superoxide dismutase. Lipid peroxidation and possible modifications in gluthatione metabolism were also studied. Weanling rats were maintained on semisynthetic diet for 6 weeks; a standard diet containing 5% (w/w) of fat as control or EVOO supplemented diets (5% and 20% w/w). Gastric lesions were induced on the last day by oral administration of indomethacin (60 mg/kg body wt). In animals fed EVOO diets, gastric lesions were decreased significantly and in parallel with dietary fat, when compared to animals consuming a standard diet. These protective effects were related to a reduction of lipid peroxides generation, neutrophil infiltration, and xanthine oxidase activity. Superoxide dismutase, an important enzyme to scavenger of lipid peroxides, was unaffected by feeding conditions. On the other hand, dietary supplementation with EVOO significantly increased both glutathione peroxidase activity and total glutathione content. In conclusion, this study provides evidence that fat diets containing EVOO reduces indomethacin-induced gastric damage in rats. This effect may be partly due not only to reducing oxidative stress and neutrophil-induced toxicity but also to enhancing the glutathione antioxidant defense system.