The purpose of this investigation was to compare the effects of initial resuscitation with HBOC-201 to that of lactated Ringer (LR) solution in the setting of uncontrolled hemorrhage and traumatic brain injury (TBI). Anesthetized immature swine underwent fluid-percussion TBI and liver laceration. During a 75-min "prehospital phase," the animals were resuscitated with HBOC-201, LR solution, or nothing (NON). Upon "hospital arrival," the animals were provided blood and 0.9% NaCl as needed, and the liver injury was repaired. Surviving animals were killed 6 h after injury. Brain tissue was processed for blood flow, and gross, light microscopic, and immunohistochemical analyses. Mean TBI force (2.6 +/- 0.6 atm) and blood loss (64.4 +/- 3.4 mL/kg) were similar between groups. Six-hour survival was significantly greater in HBOC-201 (8 of 13 [62%]) versus LR solution (1 of 11 [9%]) and NON (1 of 8 [3%]) animals (P < 0.02). Mean arterial pressures, cardiac indices, cerebral perfusion pressures, and brain tissue oxygen tension were significantly greater, and lactate and base deficit were lower in HBOC-201 as compared with LR solution animals. Blood transfusion requirements were reduced in HBOC-201 (3.6 +/- 0.6 mL/kg per survival hour) as compared to 7.1 +/- 1.2 mL/kg per survival hour. Severity of subarachnoid and intraparenchymal hemorrhages was statistically greater in LR solution-treated animals, but these differences were not likely to be clinically significant. There were no differences in glial fibrillary acidic protein and microtubule-associated protein 2. In this model of combined uncontrolled hemorrhage and TBI, initial resuscitation with HBOC-201 resulted in significant improvements in survival and systemic and cerebrovascular physiological parameters, as well as a reduction in transfusion requirements.