Abstract: Methods are provided for the preparation of an RBC composition which has significantly reduced antigenicity. The methods of preparation of the red cell compositions involve the optimization of reaction conditions, in particular buffering conditions, for attaching antigen masking compounds to the red cells without significantly affecting the function of the red cells. The RBC compositions are of particular use for introduction into an individual in cases where the potential for an immune reaction is high, for example in alloimmunized blood recipients or in trauma situations where the possibility of transfusion of a mismatched unit of blood is higher. The RBC compositions of this invention provide a much lower risk of a transfusion associated immune reaction.