The abnormal adhesion of sickle red blood cells (RBC) to the post capillary endothelium is thought to contribute to the periodic vaso-occlusive episodes characteristic of sickle cell disease. Using cultured human microvascular endothelial cells (MEC) assembled into a parallel-plate model of a blood vessel, we have investigated the adhesion of sickle RBC to MEC under flow conditions which typity the shear stresses found in the post capillary venules. Results from 40 sickle patients indicate that sickle red cells are 7.5-fold more adhesive than normal red cells in the presence of autologous plasma. When suspended in ABO blood-type, Rh-factor cross matched normal versus sickle plasma, sickle RBC adhesion to MEC decreases by 69%. When sickle plasma is depleted of collagen-binding proteins, autologous plasma mediated sickle RBC adhesion to MEC decreases by 62%. These results indicate that the sickle plasma milieu is largely responsible for the abnormal adhesion of sickle RBC to MEC in our assay. Subsequent preliminary experiments indicate that sickle, but not normal, RBC adhesion to MEC is mediated by supernatant obtained from activated platelets. These results indicate that platelets may be a source of adhesive factors in sickle plasma, possibly linking the enhanced coagulation and fibrinolytic system found in sickle cell disease (Ofasu, et al., FASEB, 1991. abstr.) to microvascular occlusive episodes in sickle cell disease.