The insult from severe hemorrhage is a multifactorial injury involving ischemia/reperfusion with inflammatory dysfunction. Our laboratories and others have demonstrated that the administration of exogenous carbon monoxide (CO) at low concentrations provides cytoprotection in vivo and in vitro. The purpose of these investigations was to test the hypothesis that CO protects against hemorrhagic shock- and resuscitation-induced systemic inflammation and end-organ damage. C57BL/6 mice underwent anesthesia and arterial cannulation. Mice were bled to reach a mean arterial pressure (MAP) of 25 mmHg and were maintained at this pressure for 2.5 h. Mice were then resuscitated with shed blood plus two times the volume of shed blood with Ringer's lactate. Sham animals were not bled. Additionally, mice were maintained in room air or in an environment of CO (250 parts per million). Primary mouse hepatocytes were harvested and used for in vitro cell viability and ATP measurement. These data demonstrate that delivery of a low concentration of inhaled CO protects against the development of end-organ injury decreases serum levels of inflammatory cytokines and increases serum levels of the anti-inflammatory cytokine IL-10. Additionally, CO paradoxically abrogates hemorrhage-induced hepatic cellular hypoxia. Furthermore, CO protected mouse hepatocytes from hypoxia-induced death while maintaining normal ATP levels. CO protects against systemic effects of hemorrhagic shock and resuscitation. The precise cellular mechanisms involved require further elucidation. CO may prove to be an adjunctive therapy that could be instituted rapidly and with ease as an out-of-hospital therapeutic modality for severe blood loss after trauma.