Low oxygen affinity red cells were prepared by incorporating inositol hexaphosphate (IHP) into red blood cells (rbc) by means of a liposomal transport system. The effect of in vitro simulated exchange transfusions on sickling was studied with buffered red cell suspensions containing 50% SS cells and 50% test cells. Test rbc were either stored cells with high oxygen affinity, fresh cells with normal affinity or IHP-loaded cells with decreased affinity. Oxygen equilibrium curves and percentage sickling as a function of PO2 were determined and the data analyzed in terms of percentage sickling as a function of oxygen delivery. Our simplified analysis shows that simulated exchange transfusion with stored and, to a lesser extent even with fresh blood, results in a decreased venous PO2 and increased sickling of the remaining SS cells. In contrast, transfusion with IHP-loaded cells results in higher venous PO2 values and less sickling throughout the range of oxygen delivery. Thus, the transfusion of IHP-loaded cells may result in less sickling of the remaining SS cells in addition to the normal dilutional effect.