This study examined whether or not a pretreatment with dehydroepiandrosterone (DHEA) has an effect on indomethacin-induced gastric mucosal damage. The DHEA group, male Sprague-Dawley rats, was administrated with DHEA orally at a dose of 4 mg/day for one week before inducing gastritis with indomethacin (50 mg/kg, p.o.). Histological assay, lipid peroxidation assay, superoxide dismutase (SOD), glutathione peroxidase (GPx) and Catalase activities were determined. Interestingly, it was found that the DHEA pretreatment attenuated the gastric lesion area induced by indomethacin. Rather, the pretreatment with high dose of DHEA led to submucosal edema, leukocyte infiltration in submucosa and mucosal necrosis. The levels of MDA in the DHEA pretreatment were also higher than those in the rats given with vehicle pretreatment. This suggests that the DHEA pretreatment deteriorates severe inflammation in indomethacin-induced gastritis. DHEA supplementation significantly increased SOD activity in the gastric mucosa. However, the catalase and GPx activities were not altered by DHEA. The co-administration of DHEA with an indomethacin might not offer a protective effect against the acute gastritis induced by indomethacin.