The aim of this study is to define the putative role of complement activation and mucosal mast cell (MMC) degranulation in the pathogenesis of rapid ischemia-reperfusion (I/R) injury. We prepared complement activity-depleted rats by the administration of the anti-complementary agent K-76COONa. To assess the role of MMC degranulation, we used the MMC stabilizer MAR-99 and genetically mast cell-deficient Ws/Ws rats. Autoperfused segments of the jejunum were exposed to 60 min of ischemia, followed by 60 min reperfusion. The epithelial permeability was assessed by <sup>51</sup>Cr-EDTA clearance rate, and the number of MMC was immunohistochemically assessed. I/R treatment induced a marked increase in mucosal permeability and MMC degranulation. The treatment with K-76COONa and MAR-99 significantly attenuated these changes. Furthermore, in Ws/Ws rats the increase in mucosal permeability and MMC degranulation was significantly attenuated. These findings indicate the role of complement activation and MMC activation in the pathogenesis of rapid intestinal I/R injury. A regulation of the complement activation and MMC degranulation may be one of the clinical strategies for prevention of I/R-induced mucosal injury.