Hemorrhage remains a common cause of death despite the recent advances in critical care, in part because conventional resuscitation fluids fail to prevent lethal inflammatory responses. Here, we analyzed whether ethyl pyruvate can provide a therapeutic anti-inflammatory potential to resuscitation fluids and prevent organ damage in porcine hemorrhage. Adult male Yorkshire swine underwent lethal hemorrhage with trauma and received no resuscitation treatment or resuscitation with Hextend alone, or supplemented with ethyl pyruvate. Resuscitation with ethyl pyruvate did not improve early hemodynamics but prevented hyperglycemia, the intrinsic coagulation pathway, serum aspartate aminotransferase, and myeloperoxidase in the major organs. Resuscitation with ethyl pyruvate provided an anti-inflammatory potential to restrain serum TNF and high-mobility group B protein 1 levels. Ethyl pyruvate inhibited nuclear factor [kappa]B in the spleen but not in the other major organs. In contrast, ethyl pyruvate inhibited NO in all the major organs, and it also inhibited TNF production in the major organs but in the lung and heart. The most significant effects were found in the terminal ileum where ethyl pyruvate inhibited cytokine production, restrained myeloperoxidase activity, preserved the intestinal epithelium, and prevented the systemic distribution of bacterial endotoxin. Ethyl pyruvate can provide therapeutic anti-inflammatory benefits to modulate splenic nuclear factor [kappa]B, restrain inflammatory responses, and prevent hyperglycemia, the intrinsic coagulation pathway, and organ injury in porcine hemorrhage without trauma.