Natural acellular polymeric hemoglobins (Hb) provide oxygen transport and delivery within many terrestrial and marine invertebrate organisms. It has been our premise that these natural acellular Hbs may serve as models of therapeutic hemoglobin-based oxygen carriers (HBOC). Our attention has focused on the acellular Hb from the terrestrial invertebrate, Lumbricus terrestris (Lt), which possesses a unique hierarchical structure and a unique ability to function extracellularly without oxidative damage. Lumbricus Hb and Arenicola Hb are resistant to autoxidation, chemical oxidation by potassium ferricyanide, and have little or no capacity to transfer electrons to Fe(+3)-complexes at 37 degrees C. An understanding of how these invertebrate acellular oxygen carriers maintain their structural integrity and redox stability in vivo is vital for the design of a safe and effective red cell substitute. We report here a positive redox potential for these giant hemoglobins that may lie at the basis for its resistance to oxidation.