The contribution of the reticuloendothelial system (RES) in pyridoxalated stroma-free hemoglobin (SFH-P) clearance may be insignificant. The magnitude of this is not at present clear. Any compromise of RES function would militate against its potential benefit as an oxygen-carrying resuscitation fluid. The relationship between lethal hemorrhagic shock resuscitation with SFH-P and subsequent host depression was examined in a rat model. Host tolerance to a standard intra-abdominal polymicrobial septic challenge was assessed 5 days after hemorrhagic shock. Shock resuscitation with pyridoxalated stroma-free hemoglobin was equal to or better than all other resuscitation groups evaluated. Tolerance to a standard septic challenge 5 days after resuscitation was no different between resuscitation groups. There appears to be no compromise to host defense in general in tolerating intra-abdominal sepsis 5 days following shock resuscitation with pyridoxalated stroma-free hemoglobin.