This study was designed to determine whether repeated exposures to stress lead to the adaptation of the gastric mucosa to stress ulcerogenesis. Wistar rats with intact or resected salivary glands were exposed to a standard period (3.5 h) of water-immersion and restraint stress every other day up to 8 days. The significant reduction in the severity of gastric lesions was first noticed after the second exposure to stress and was maximal after 6-day exposures to stress. This tolerance to stress ulcerogenesis disappeared after a 6-day rest during which animals were not exposed to stress. Histologically, the hemorrhages and edema seen after a single stress were less frequent during adaptation; instead the mucosa regenerated in spite of continuation of exposure to stress. During adaptation, the mucosal blood flow (MBF) and mucosal biosynthesis of PG were markedly increased. Administration of indomethacin (5 mg/kg i.p.) completely abolished gastric adaptation to stress and this was accompanied by about 85% reduction in mucosal generation of PG and significant decrease in the MBF. Salivectomy, which significantly reduced the luminal contents of epidermal growth factor (EGF) in the stomach, delayed and reduced the adaptation. We conclude that the stomach has the ability to adapt to repeated exposures to stress and that this adaptation is mediated, at least in part, by endogenous PG and EGF.