Background The ideal resuscitation fluid for military applications would be effective at low volumes, thereby reducing logistical constraints. We have previously shown that the bovine hemoglobin-based oxygen carrier HBOC-201 is an effective low-volume resuscitation fluid. The goal of this experiment was to evaluate the effectiveness of HBOC-201 in comparison with other low-volume resuscitation fluids in a swine model of controlled hemorrhagic shock. Methods Forty-two immature female Yorkshire swine (55-70 kg) were divided into seven groups of six. Animals were hemorrhaged to a mean arterial pressure of 30 mm Hg. After 45 minutes, animals were resuscitated to a mean arterial pressure of 60 mm Hg with one of the following agents; hypertonic saline 7.5% (HTS), hypertonic saline 7.5%/Dextran-70 6% (HSD), pentastarch 6%, hetastarch 6%, or HBOC-201. Lactated Ringer’s (LR) solution was used as a standard resuscitation control. Another group of animals received no resuscitation. Resuscitation was continued for 4 hours. Hemodynamic variables and oxygen consumption were measured continuously. Arterial and mixed venous blood gases and serum lactate levels were measured at intervals throughout the experiment. Data were analyzed using analysis of variance with Tukey’s post hoc test when appropriate. Significance was defined as p < 0.05. Results Five of six animals in the no-resuscitation control group, six of six in the HTS group, and one animal in the HSD group died before completion of the study. All other animals survived to completion. Animals receiving resuscitation with HBOC-201 had significantly lower cardiac output, mixed venous oxygen saturation levels, and urinary output throughout the resuscitation period; however, there were no differences with regard to lactate, base excess, or oxygen consumption. Animals receiving HBOC-201 required significantly less fluid than any other group. Conclusion In this model, hypotensive resuscitation with HBOC-201 restores tissue oxygenation and reverses anaerobic metabolism at significantly lower volumes when compared with HTS, HSD, pentastarch, or hetastarch solutions. These data suggest that HBOC-201 would be an effective primary resuscitation fluid for far-forward military or rural trauma settings where logistic constraints and prolonged transport times are common. However, when HBOC-201 is administered as a primary resuscitation fluid in hypotensive protocols, common clinical markers for determining adequacy of resuscitation may not be useful. © 2003 Lippincott Williams and Wilkins, Inc.