There is good evidence that endotoxemia, sepsis, and septic shock are associated with the generation and release of reactive oxygen species (ROS) such as superoxide anion (O2), indicating that oxygen-derived free radicals play an important role in the pathogenesis of sepsis/shock. Studies on the application of free oxygen radical scavengers to limit the damage to tissues and organs have been recently attempted. A stable piperidine nitroxide of low molecular weight (Tempol) can permeate biological membranes and scavenge O2 in vitro and in vivo. Thus, we investigated effects of Tempol on the circulatory failure and multiple organ injuries caused by a clinically relevant polymicrobial sepsis model in the rat-cecal ligation and puncture (CLP). CLP not only successfully induced circulatory failure but also substantially increased plasma concentrations of glutamate-oxalate-transferase and glutamate-pyruvate-transferase (indicators of liver injury), creatinine and blood urea nitrogen (indicators of kidney injury), and decreased base excess in arterial blood in the late stage, indicating the development of multiple organ injury in this study. These were also confirmed by a histologic examination showing that the CLP-induced sepsis accompanied increase of polymorphonuclear neutrophil (PMN) infiltration in the lung and sequestration in the liver. Our results demonstrated that Tempol not only ameliorated the deterioration of hemodynamic changes and renal and liver injuries but also attenuated PMN infiltration in the lung and sequestration in the liver (histology). In addition, Tempol improved the survival in CLP-induced septic rats. Moreover, Tempol reduced the plasma NO. and interleukin-1beta and organ O2 levels in CLP-treated rats. In conclusion, Tempol prevented circulatory failure and attenuated organ dysfunction/injury as well as decreased the mortality rate in CLP-treated animals. These beneficial effects of Tempol may be attributed to inhibition of ROS formation (e.g., NO. and O2), suggesting antioxidant (e.g., Tempol) is a potential therapeutic agent in the treatment of intraperitoneal septic shock.