Cell-free hemoglobin increases systemic and pulmonary pressure and resistance and reduces cardiac output and heart rate in animals and humans, effects that have limited their clinical development as "blood substitutes". The primary aim of this study was to evaluate the hemodynamic response to infusion of several formulations of a new PEG-modified human hemoglobin (MalPEG-Hb) in swine, an animal known to be sensitive to hemoglobin-induced vasoconstriction. Anesthetized animals underwent controlled hemorrhage (50% of blood volume), followed by resuscitation (70% of shed volume) with 10% pentastarch (PS), 4% MalPEG-Hb in lactated Ringer's (MP4), 4 % MalPEG-Hb in pentastarch (HS4), 2 % MalPEG-Hb in pentastarch (HS2), or 4 % stroma-free hemoglobin in lactated Ringer's solution (SFH). Compared to baseline, restoration of blood volume following resuscitation was similar and not significantly different for the PS (103%), HS2 (99%), HS4 (106%) and MP4 (87%) animals but significantly less for the SFH animals (66%) (P < 0.05). All solutions that contained MalPEG-Hb restored mean arterial and pulmonary pressure and cardiac output. Systemic vascular resistance was unchanged, and pulmonary arterial pressure and resistance were increased slightly. Both systemic and pulmonary vascular resistance increased significantly in animals that received SFH, in spite of less adequate blood volume restoration. Oxygen consumption was maintained in all animals that received MalPEG-Hb, but not PS. Base excess improved only with MalPEG-Hb and PS, but not SFH. Red blood cell O₂ extraction was significantly increased in animals that received hemoglobin, regardless of formulation. These data demonstrate resuscitation with MalPEG-human Hb in the absence of systemic vasoconstriction, and support our previous observations in animals suggesting that the efficacy of low concentrations of PEG-hemoglobin in the plasma results from reduced vasoconstriction.