Multiple organ dysfunction syndrome (MODS) is the most serious complication of trauma or infection. Our previous study has shown that activated intestinal mucosal mast cells (IMMC) might play an important role in the development of MODS. Somatostatin (SST), one of the peptides derived from gut, is an important regulator in the neuroendocrine-immune network. However, the effects of SST on IMMC, especially in the situation of MODS, remain unclear. The aim of this study was to investigate the effect of SST on the activity of IMMC in MODS. A rat model of MODS was established 24 h after intraperitoneal injection of zymosan at dosage of 75 mg/kg. SST was injected into the tail vein 30 min after intraperitoneal inoculation of zymosan. Animals were sacrificed 25 h after zymosan injection. The concentration of histamine and tumor necrosis factor-alpha (TNF-alpha) in plasma and intestinal tissue was measured. The pathological changes of vital organs, including intestine, liver, kidney, and lung, were studied under light microscopy. The ultramicrostructures of IMMC were observed by transmission electron microscopy. Obvious improvement of pathological changes of vital organs was observed in the rats with MODS treated with SST at 2.3 ng/kg/h. PO2 was increased by 50% (P < 0.05). The histamine level in the intestinal tissue of rats with MODS treated with SST (14.50 +/- 1.08 ng/g protein) was significantly higher than that of the group without treatment (8.60 +/- 0.50 ng/g protein, P < 0.01). Furthermore, degranulation of IMMC in the rats treated with SST was less obvious. The in vitro inhibitive effect of SST on the histamine release rate of IMMC was negatively correlated to its concentration (r = -0.991, P < 0.01). In conclusion, suppression of IMMC activity might be an important mechanism of the protective effects of SST in rats with a high risk of MODS.