A solution of hemoglobin has several potential applications as a blood substitute. However, because of high oxygen affinity (P50 approximately 14 mm Hg) and short vascular retention time of hemoglobin (plasma half-disappearance time approximately 3.5 hr), a solution of hemoglobin presents limitations for its general use in blood replacement therapy. To overcome these limitations crystalline hemoglobin was modified by pyridoxalation and subsequent polymerization. Pyridoxalation yielded a product with a P50 ranging from 23 to 26 mm Hg. The pyridoxalated hemoglobin was then polymerized with glutaraldehyde and the final modified hemoglobin showed a P50 of 19 to 22 mm Hg. The modified hemoglobin was tested in vitro for coagulation activities. The results indicated that no adverse coagulant activity was demonstrated by the modified products. In vivo studies in the rat have shown that pyridoxalated-polymerized hemoglobin has a plasma half-disappearance time of about 25 hr. The data demonstrated that a solution of pyridoxalated-polymerized hemoglobin, because of its lower oxygen affinity and longer vascular retention than unmodified hemoglobin, has significant potential as a basis for an efficient resuscitation solution.