Abstract: A process for efficiently preparing bis-tetrameric hemoglobin in which the tetramers are specifically linked at predetermined sites on the ?-sub-units and in which the tetramers themselves are effectively bonded to prevent dissociation into dimeric ??-hemoglobin sub-units therefrom is provided. The process uses as cross-linking reagent a hexafunctional aromatic acyl phosphate containing amide groups, The concept is to use a cross-linking reagent which has an excess of site-specific hemoglobin reacting groups, namely six acyl phosphate groups, so that at least four of them will react site specifically to form the bis-tetrameric product of particular therapeutic interest.