Red blood cells (RBCs) from patients with sickle cell disease (SCD) contain abnormal haemoglobin HbS instead of normal adult HbA. Deoxygenated HbS polymerises, distorts RBCs into bizarre shapes and alters rheology. RBCs from SCD patients show high cation permeability causing solute loss, shrinkage and increasing [HbS] thus greatly encouraging polymerisation. Several pathways participate in increased permeability [1]: KCl cotransport (KCC), the Gardos or Ca2+-activated K+ channel and a deoxygenation-induced non-selective cation pathway (Psickle). The pathology of SCD is extensive but treatment remains largely supportive. Hydroxyurea has proven clinical efficacy, probably by encouraging expression of fetal Hb, HbF. However, not all patients respond equally to treatment [2]. Routine discarded blood samples were obtained from SCD patients using EDTA as an anticoagulant. RBCs were washed in saline comprising (in mM) NaCl 145, glucose 5, MOPS 10, pH 7.4, 290±5 mOsm.kg-1, 37°C. O2 tension was controlled using Eschweiler tonometry and a Wösthoff gas mixer. Activities 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) [3]. Ouabain and bumetanide were present to inhibit the Na+/K+ pump and Na+-K+-2Cl-contransporter. Cell morphology was assessed by light microscopy after RBCs were fixed in 0.3% glutaraldehyde in saline. On deoxygenation, 76±2 % (n=30) of RBC from untreated SCD patients showed sickling. The majority of RBCs from treated patients could be put into two groups – showing either less than 65% (n=11) or more than 75% (n=17) sickling. After dividing patients into two groups on the basis of the extent of deoxygenation-induced sickling (‘<70%’: 57±3%, n=12; ‘>70%’: 79±1%, n=22), we compared their HbF levels (14.4±1.8% vs. 8.3±0.9% for ‘<70%’ vs. ‘>70%’; p=0.001) and transport activities. KCC, Psickle and Gardos activities on deoxygenation were significantly reduced when the ‘<70%’ group was compared with untreated patients (p=0.009, p=0.019, p=0.018, respectively), as was KCC activity at 100mmHg (p=0.013). RBC from untreated patients and the ‘>70%’ sickling group showed no significant differences. Whilst reduction in KCC activity following hydroxyurea therapy has been previously mentioned [4], albeit in a small number of patients (n=3), beneficial effects on deoxygenation-induced Psickle and Gardos channel activity have not been hitherto described. These actions on RBC permeability may therefore elucidate further the mechanism by which hydroxyurea has its therapeutic effect. They also imply an important role for HbF levels in regulation of RBC membrane permeability.