Background: Rapid resuscitation with oxygen-carrying fluids is critically important in hemorrhagic shock (HS) combat casualties in remote areas where blood is not available. Hemoglobin-based oxygen carrier-201 (HBOC-201) has been shown to increase survival and reduce immune activation following HS in animal models. Recombinant factor VIIa (rfVIIa), a systemic hemostatic agent, is Food and Drug Administration approved for use in acute hemorrhage in hemophilic patients. The combination of HBOC-201 and rfVIIa may form the basis of a prospective multifunctional blood substitute and provide benefits in the rapid restoration of hemostasis, decreased inflammation and improved survival of HS combat casualties. In the present study, we evaluated innate immune responses in a swine model of uncontrolled HS following resuscitation with HBOC-201 ± rfVIIa. Materials: Thirty-two pigs underwent uncontrolled hemorrhage/liver crush injury, followed by resuscitation with five doses of HBOC-201 or HBOC + rfVIIa (90 μg/kg, or 180 μg/kg, or 360 μg/kg) and simulated 4 hours hospital arrival. Immune parameters were evaluated by flow cytometry and enzyme-linked immunosorbent assay. Results: Survival differences to 72 hours of animals resuscitated with HBOC, HBOC + rfVIIa (90), (180), and (360) were not statistically significant and resulted in survival of 25%, 63%, 63% and 50%, respectively. At the prehospital phase all groups exhibited minimal immunomodulation, characterized by stable CD4/CD8 ratio, marginal increase of apoptosis and insignificant fluctuations of adhesion markers; increase of plasma cytokines was comparable across all groups, except tumor necrosis factor-α, that was significantly elevated in the HBOC group. Conclusion: HBOC-201 + rfVIIa triggered minimum immune activation in an uncontrolled HS swine and there was a nonsignificant survival benefit. © 2008 by Lippincott Williams & Wilkins.