The role of leukotriene (LT) in the pathogenesis of indomethacin-induced gastric mucosal damage was investigated in rats. After administration of indomethacin, LTB4 and sulfidopeptide LT (SPLT) content in gastric mucosa were assessed by radioimmunoassay and mucosal blood flow was measured by laser-Doppler flowmetry. Indomethacin (20 mg/kg) caused visible gastric mucosal damage. Indomethacin at this dose caused marked reduction of gastric mucosal blood flow but did not affect gastric mucosal content of LTB4 and SPLT. AA-861, a selective 5-lipoxygenase, and DS-4575 and YM-683, two different SPLT receptor antagonists, inhibited both mucosal damage and reduction of mucosal blood flow. These results suggested that endogenous LT, especially SPLT, may be involved in the indomethacin-induced mucosal damage via the reduction of gastric mucosal blood flow.