Complications in sickle syndromes are thought to result from regional disturbances of normal blood flow with subsequent ischemic damage. Adherence of sickle erythrocytes has been implicated in the pathophysiology of occlusive complications. Most previous studies have explored adherence of sickle erythrocytes to endothelial cells from large vessels, even though the majority of the pathophysiologic models implicate the microvascular system. To explore potential variation in endothelial interactions at low shear rates, adherence of sickle erythrocytes to large vessel umbilical vein endothelium and microvascular endothelium was compared under flow conditions in a parallel-plate flow chamber at a shear stress of 1.0 dyne/cm2. Autologous plasma promotes high levels of sickle red cell adherence to microvascular endothelial cells, but only low levels of adherence to human umbilical vein endothelium. On average, autologous plasma promotes sixfold more sickle cell red adherence to microvascular endothelial cells. In contrast to umbilical vein endothelium, high molecular von Willebrand factor does not elevate sickle cell adherence to microvascular endothelial cells, and the integrin receptor agonist peptide, RGD, does not inhibit adherence to microvascular endothelial cells. These results demonstrate that sickle erythrocyte adherence to large vessel and microvascular endothelium is quantitatively and qualitatively different and that plasma factors may have significant impact on sickle erythrocyte adherence to endothelium in the microvessels. Since microvascular occlusion has been suggested as an antecedent of ischemic damage in sickle syndromes, plasma enhanced adherence to microvascular endothelium may contribute to the pathophysiology of episodic occlusion in sickle cell anemia.