Hemoglobin ζ 2 β 2 S is generated by substituting embryonic ζ-globin subunits for the normal α-globin components of Hb S ( α 2 β 2 S ) . This novel hemoglobin has recently been shown to inhibit polymerization of Hb S in vitro and to normalize the pathological phenotype of mouse models of sickle cell disease in vivo. Despite its promise as a therapeutic tool in human disease, however, the basic O 2-transport properties of Hb ζ 2 β 2 S have not yet been described. Using human hemoglobins purified from complex transgenic-knockout mice, we show that Hb ζ 2 β 2 S exhibits an O 2 affinity as well as a Hill coefficient, Bohr response, and allosteric properties in vitro that are suboptimally suited for physiological O 2 transport in vivo. These data are substantiated by in situ analyses demonstrating an increase in the O 2 affinity of intact erythrocytes from mice that express Hb ζ 2 β 2 S . Surprisingly, though, co-expression of Hb ζ 2 β 2 S leads to a substantial improvement in the tissue oxygenation of mice that model sickle cell disease. These analyses suggest that, in the context of sickle cell disease, the beneficial antisickling effects of Hb ζ 2 β 2 S outweigh its O 2-transport liabilities. The potential structural bases for the antisickling properties of Hb ζ 2 β 2 S are discussed in the context of these new observations.