Sickle red blood cells (RBC) suspended with endothelial cell (EC)-derived unusually large (UL) von Willebrand factor (vWF) multimers, but not large plasma vWF forms, adhered to human venous EC under shear flow conditions. When sickle RBC were separated by density gradient centrifugation, fractions rich in less dense RBC were the most adhesive to EC in the presence of ULvWF. Incubation of sickle RBC with monoclonal antibodies against platelet surface receptors GPIb or GPIIb/IIIa, or with the integrin receptor agonist Arg-Gly-Asp-Ser (RGDS) decreased the ULvWF-mediated sickle RBC adhesion to EC 84%, > 99%, and 90%, respectively. When incubated with EC before the flow studies, anti-GPIb antibody and RGDS inhibited the ULvWF-mediated sickle RBC adhesion to EC. ULvWF also promoted the adhesion to EC of nonsickle RBC (HbAA) from patients with an increased proportion of young erythrocytes. When the EC supernatant was depleted of most vWF forms, young nonsickle RBC adhesion decreased by 90%. Preincubation of young nonsickle RBC with anti-GPIb antibody, anti-GPIIb/IIIa antibody, or RGDS inhibited the ULvWF-mediated young RBC adhesion to EC by 47%, 88%, and 92%, respectively. These data indicate that (1) low-density erythrocyte fractions enriched in young sickle or young nonsickle RBC are capable of binding ULvWF multimers via GPIb-like and GPIIb/IIIa-like receptors; (2) the RBC vWF receptors are lost or modified as erythrocytes age in the circulation; and (3) ULvWF/RBC complexes also bind to EC via a GPIb-like receptor.