The major cause of morbidity and mortality in sickle cell disease (SCD) is tissue ischemia and infarction due to vascular obstruction. One of the most devastating vascular complications of SCD is clinical stroke caused by occlusion of the large cerebral arteries in the Circle of Willis or its branches. Overt stroke occurs with obvious speech or motor deficits in approximately 10% of children with SCD. Additional complications due to stroke in SCD include an increased risk of secondary disabilities such as mental retardation and learning disabilities, with the most severe forms of neurocognitive impairments associated with large vessel disease (overt stroke). When compared to normal RBCs, sickle red blood cells (SS-RBCs) have markedly increased adhesion to the vascular endothelium and several subendothelial matrix proteins. The increased sickle RBC adhesion likely plays a significant role in the pathogenesis of vascular obstruction. We have previously shown that SS-RBCs have enhanced adhesion to the plasma and extracellular matrix protein thrombospondin-1 (TSP) under conditions of flow in vitro. In addition, we have observed that the level of adhesion of RBC adhesion varies from patient to patient (i.e., there are some patients whose RBCs tend to consistently be “stickier” or “less sticky” than other patients). In this study, we proposed that patients who develop large vessel (Circle of Willis and major branches) central nervous system (CNS) disease (e.g., clinical stroke) have higher baseline levels of RBC adhesion. Thus, we examined the level of sickle RBC adhesion to immobilized TSP under flow conditions from patients with SCD with and without stroke. We recruited 87 male and female patients over the age 3 yrs with HbSS disease from the Wisconsin Sickle Cell Disease Comprehensive Center. Of these, 8 patients later developed an overt stroke following their participation in this study. None of the patients were transfused prior to studying RBC adhesion. After obtaining informed consent, blood samples were collected into citrate from patients with HbSS disease. Washed RBCs were perfused through flow chambers previously coated with TSP (2 μg/cm2) at a wall shear stress of 1 dyne/cm2 that mimics the forces in post-capillary venules and optimizes sickle RBC adhesion. After rinsing, adherent RBCs per unit area were counted in four random fields in each of two duplicate wells by direct microscopic visualization. We found that patients with SCD who developed an overt stroke (n=8) had a higher level of RBC adhesion (1436 ±101 RBCs/mm2) compared to 79 unselected patients with SCD who had a mean RBC adhesion of 1004 ± 53 RBCs/mm2 (p=0.016, student t-Test). Thus, RBCs derived from the subpopulation of patients with SCD who developed an overt stroke associated with large vessel disease have an abnormally enhanced adhesive phenotype. These data suggest that enhanced levels of RBC adhesion may play a role in the development of large vessel disease in SCD.