The efficacy of Diaspirin Crosslinked Hemoglobin (DCLHb) as a resuscitative fluid in hemorrhagic shock was compared to another colloid solution (human serum albumin, HSA) and a crystalloid solution (Lactated Ringer's, LR). Hemorrhage (35 mL/kg) was followed by isovolemic exchange then volume replacement. This modeled the clinical situation where resuscitative fluids are administered prior to stopping the hemorrhage, the hemorrhage is stopped, then blood volume is restored. Four combinations of resuscitative fluids were evaluated during isovolemic exchange: volume replacement: DCLHb:LR, HSA:LR, HSA:HSA and LR:LR. All doses were 10 mL/kg:35 mL/kg except LR:LR which was 10 mL/kg:125 mL/kg. Volume replacement was followed by a stabilization period and reinfusion of shed blood (35 mL/kg). MAP increased most rapidly using DCLHb (from 48 to 102 mmHg after 10 min of isovolemic exchange) and was maintained for at least 2 hours. Arterial oxygen content and acid-base status were significantly improved after resuscitation with DCLHb:LR vs. other resuscitative therapies. In conclusion, DCLHb:LR was an effective resuscitative therapy in treatment of hemorrhagic shock.