Background: Decreased mesenteric blood flow and multiple organ injury due to free radicals are the consequences of septic shock. Since the blockade of endothelin receptors was reported to exert beneficial effects, we investigated the effects of tezosentan, a novel dual endothelin receptor antagonist, in two different experimental models of septic shock induced either by the injection of Escherichia coli endotoxin (ETX, 20 mg/kg, i.p.) or by cecal ligation and puncture (CLP). Study design: Swiss albino mice received tezosentan (10 mg/kg, i.p.) or its solvent saline (0.9% NaCl, w/v) twice at 2 and 22 h after ETX or CLP. At 24 h, the animals were anesthetized and the mesenteric blood flow was monitored for 15 min by using perivascular ultrasonic Doppler flowmeter. Then the animals were exsanguinated, and spleen, liver, and kidneys were isolated accordingly for histopathological examination. Thiobarbituric acid reacting substances and glutathione and myeloperoxides activities were also determined in the liver. Results: In both ETX and CLP models, there was a decrease in mesenteric blood flow which was blocked by tezosentan. Similarly, tezosentan significantly attenuated the histopathological injury inflicted by both models. Although the glutathione levels were decreased and thiobarbituric acid reacting substances and myeloperoxidase activity were increased by ETX and CLP, tezosentan has failed to block these alterations in a consistent manner. However, a significant interaction between CLP and tezosentan with regard to myeloperoxidase activity and glutathione should be taken as partial evidence to explain the underlying mechanism of protection offered by tezosentan against liver injury. Conclusions: Therefore, we concluded that tezosentan, by working via mechanisms mostly other than the blockade of free radical induced damage, is a useful treatment option for combating the deleterious effects of septic shock such as mesenteric ischemia as well as liver, spleen, and kidney injury. © 2007 Elsevier Inc. All rights reserved.