This study was designed to evaluate the protective effect of amifostine on indomethacin-induced gastric damage, and the role of increased gastric non-protein sulfhydryl groups (NP-SH) and decreased leukocyte adherence in this event. Wistar rats were pretreated with amifostine (10, 30, or 90 mg/kg intraperitoneal (i.p.) or subcutaneous (s.c.)) or saline. After 30 min, the rats received indomethacin (20 mg/kg, by gavage) and were then killed 3 hr later. Macroscopic and microscopic gastric damage, concentration of gastric NP-SH, prostaglandin E2 (PGE2), and mesenteric leukocyte adherence (intravital microscopy) were assessed. Amifostine prevented significantly (P < 0.05), macroscopic or microscopic, indomethacin-induced gastric damage, and increased gastric NP-SH, in a dose-dependent manner, with a maximal effect at a dose of 90 mg/kg. Subcutaneous, but not i.p., amifostine administration decreased (P < 0.05) the indomethacin-induced increase in leukocyte adherence. Indomethacin-induced PGE2 depletion was not reversed by amifostine. Amifostine has a protective effect against indomethacin-induced gastropathy by increasing gastric NP-SH and decreasing leukocyte adherence.