The phosphatidylcholine specific transfer protein (PCTP) from bovine liver was used to retailor the molecular species composition of phosphatidylcholine (PC) in the membrane of normal (AA) and sickleable (SS) human erythrocytes. Changes in molecular species composition of PC altered morphology as well as cellular deformability and stability as measured with ektacytometry. In normal cells, replacement of native PC with 1-palmitoyl,2-arachidonoyl PC (PAPC) resulted in a decrease in osmotic fragility with no change in hydration, whereas replacement with 1,2-dipalmitoyl PC (DPPC) led to an increased osmotic fragility and cellular hydration. Replacement of native PC by 1-palmitoyl,2-oleoyl PC (POPC) in normal cells had no apparent effect on these parameters. In contrast, replacement of native PC in sickle cells with either PAPC, DPPC or POPC led to cellular hydration. Facilitation of PC exchange between subpopulations of SS cells separated on buoyant density also led to cellular hydration. These observations suggest that the state of hydration of sickle cells can be modified by the fatty acyl composition of PC and illustrate a a role for the lipid core in the observed permeability changes in sickle erythrocytes. They also raise the interesting possibility that the state of cellular hydration of sickle cells may be modulated by altering the molecular species composition of the membrane phospholipids.