Reactive oxygen species contribute to the multiple organ dysfunction syndrome in hemorrhagic shock. Here, we investigate the effects of two chemically distinct inhibitors of NADPH oxidase on the circulatory failure and the organ dysfunction and injury associated with hemorrhagic shock in the anesthetized rat. Hemorrhage (sufficient to lower mean arterial blood pressure of 45 mmHg for 90 min) and subsequent resuscitation with shed blood resulted (within 4 h after resuscitation) in a delayed fall in blood pressure and in renal dysfunction and liver injury. Treatment of rats upon resuscitation with the NADPH oxidase inhibitors diphenylene iodonium (DPI, 1 mg/kg i.v.) reduced renal dysfunction and liver injury, whereas apocynin (3 mg/kg i.p.) did reduce the liver injury, but not the renal dysfunction caused by hemorrhagic shock. DPI and apocynin also attenuated the lung and intestinal injury (determined by histology) caused by hemorrhage and resuscitation. In the liver, DPI and apocynin abolished the increase in the formation of superoxide anions associated with hemorrhagic shock. However, neither DPI nor apocynin had a significant effect on the delayed circulatory failure caused by hemorrhage and resuscitation. In addition, DPI and apocynin did not reduce the increase in nitric oxide synthesis caused by hemorrhagic shock. Moreover, DPI reduced the activation of the transcription factor activator protein-1 caused by severe hemorrhage and resuscitation in the liver. Thus, we propose that an enhanced formation of superoxide anions by NADPH oxidase contributes to the liver injury caused by hemorrhagic shock, and that inhibitors of NADPH oxidase may represent a novel therapeutic approach for the therapy of hemorrhagic shock.