Methyl acetimidate has been shown to be an effective in vitro antisickling agent with few detrimental effects on the red cell. 51Cr-survival of red cells that had been incubated in vitro with methyl acetimidate was prolonged to near normal levels in sickle cell anemia patients. However, some patients developed an immune response following multiple reinfusions of the acetamidinated cells. Pre-equilibration of erythrocytes with the membrane-impermeable aldehyde, pyridoxal 5'-phosphate, prior to the addition of methyl acetimidate to the reaction mixture, has been shown to prevent agglutination of acetamidinated cells which were resuspended in immune serum. However, the protection was not extensive enough to prevent an immune response in a sickle cell anemia patient who had already been sensitized against acetamidinated cells. It is apparent that further consideration of imidoesters as extracorporeal antisickling agents will require complete protection of membrane amino groups against reaction with the imidoester.