Red blood cells (RBCs) from patients with sickle cell disease (SCD) contain the abnormal haemoglobin HbS instead of the normal adult HbA [4]. Deoxygenated HbS polymerises, distorts RBCs into bizarre shapes and alters rheology. The resulting pathology is extensive but treatment remains largely supportive. Severely affected individuals, however, are sometimes given hydroxyurea which ameliorates SCD complications probably by encouraging expression of fetal Hb, HbF. RBCs from SCD patients show high cation permeability which causes solute loss, shrinkage and increased [HbS]. As the lag time to polymerisation is inversely proportional to a very high power of [HbS], modest shrinkage is sufficient to encourage greatly HbS polymerisation and thereby contributes to disease. Several pathways participate in the increased permeability [3]: KCl cotransport (KCC), the Gardos or Ca2+-activated K+ channel and a deoxygenation-induced non-selective cation pathway (Psickle). Psickle mediates Ca2+ entry, activating the Gardos channel and causing phospholipid scrambling. There is little information on how hydroxyurea alters these parameters [1]. Routine discarded blood samples were obtained from SCD patients using EDTA as anticoagulant. RBCs were washed in saline comprising (in mM) NaCl 145, glucose 5, MOPS 10, pH 7.4, 290±5mOsm.kg-1, 37oC (unless stated otherwise). O2 tension was controlled using Eschweiler tonometry and a Wösthoff gas mixer. The activity of the main transport pathways were measured using 86Rb+ as a K+ congener (KCC as the Cl–dependent flux replacing Cl- with NO3-, Gardos channel as the clotrimazole (CLT 5µM)-sensitive flux, Psickle as Cl–independent, CLT-insensitive flux) [2]. Ouabain and bumetanide were present to inhibit the Na+/K+ pump and Na+-K+-2Cl- cotransporter. Phosphatidylserine (PS) exposure was measured using FITC-lactadherin by FACS. Haemolysis was measured in isosmotic sucrose solution (salts replaced with sucrose). Cell morphology was assessed under light microscopy after fixing in saline plus 0.3% glutaraldehyde. Compared to untreated SCD patients, RBCs in those given hydroxyurea showed a reduced percentage of sickled cells on deoxygenation (Fig 1a). Psickle, Gardos channel and KCC activtiy were also all inhibited (Fig 1a & 1b). In addition, KCC showed greater O2 dependence (Fig 1b). RBCs were also protected by about 50% against haemolysis in isosmotic sucrose solution. Finally, deoxygenation-induced PS exposure appeared unaffected. Findings increase our understanding of how treatment with hydroxyurea, and increased expression of HbF, protect RBCs from SCD patients from some of the deleterious consequences of the presence of HbS. It is possible that some of these RBC phenotypes are involved in amelioration of the complications of SCD.