A hybrid erythrocyte model for membrane studies in sickle cell disease has been developed. The model consists of normal red cell membranes containing hemoglobin S and sickle cell membranes containing hemoglobin A. In hybrids, complete hemoglobin exchange has been achieved together with restoration of low membrane permeability to potassium. Normal membranes containing HbS sickle upon deoxygenation and assume the characteristic appearance of irreversibly sickled cells (ISC) after prolonged anoxia. It is suggested that the hybrid model will be useful in defining further the process of ISC formation and in studying the influence of sickle hemoglobin upon the function of the surrounding membrane.