We have proposed new criteria for a successful cell-free, hemoglobin-based O2 carrier. These include increased molecular radius, increased viscosity, increased oncotic pressure, and reduced p50. A new molecule, MalPEG-Hb, formulated at 4.2g/dL in lactated Ringer's solution (MP4), has been produced according to these new criteria. MP4 has a p50 of 5-6 mm Hg, oncotic pressure of 49mm Hg and viscosity of 2.2cPs. After 50% exchange transfusion with MP4, rats survive a 60% controlled hemorrhage in spite of total hemoglobin of 7.8 g/dL and plasma hemoglobin concentration of 1.6 g/dL. This model results in 50% mortality in control animals and 100% mortality in animals exchange-transfused with either crosslinked or polymerized hemoglobin. Oxygen supply to tissue was measured directly in the hamster skinfold model, in which O2 release in precapillary and capillary vessels can be quantified. The data demonstrate that the effectiveness of MP4 results from its ability to conserve O2 in precapillary vessels and release O2 in capillaries, thereby "targeting" O2 to hypoxic tissue. Preservation of functional capillary density and prevention of vasoconstriction further contribute to the effectiveness of this new formulation.