Abstract Objective: This study was undertaken to evaluate the changes of the activity of the intestinal mucosal mast cells (IMMC) in multiple organ failure (MOF). Methods: Rat model of the MOF was induced by intraperitoneal injection of zymosan. Both the functional alteration and the pathological morphology of essential organs, including small intestine, liver, kidney and the lungs, were examined, or visualized by light microscopy. The histamine and tumor necrosis factor α (TNF-α) in plasma and small intestinal tissue were detected by the fluorimetric assay and Enzyme-linked immunoadsordent assay, respectively. The ultra structure changes of the IMMC from MOF rat were evaluated by a transmission electronic microscope. Results: Zymosan induced obvious inflammatory morphology and functional impairment in the essential organs in the rats, which is indicative of characteristic changes in the MOF. It showed a significant decreased level of histamine in the intestinal tissue of the MOF rats when compared with the normal controls (11.63±1.97 vs 8.67±1.16 ng/g protein, P<0.01), whereas the plasma histamine level no significant changes. TNF-α level elevated apparently in both intestinal tissue and plasma in MOF rats. Furthermore, the increased number and degranulation of IMMC in the gut tissue were obvious in the MOF rats. Conclusion: These results suggested that the histamine and TNF-α, released from irrelevantly activated IMMC, may play an important role in the development of MOF.