Venular microvascular circulation in patients with sickle cell anemia exhibits reduced and episodic blood flow. Sickle erythrocyte adhesion to postcapillary venule endothelium is postulated to initiate and propagate episodes of vasoocclusive pain. Hemodynamics likely mediate the adherence of sickle cells to endothelium, controlling delivery of potentially adherent erythrocytes and removal of loosely adherent erythrocytes on the endothelium. This study found a high dependence on shear stress of sickle erythrocyte adhesion to vascular cell adhesion molecule-1 (VCAM-1) on endothelium stimulated by tumor necrosis factor-α (TNF-α). Shear stress varied from 1.0 dyne/cm2(microvascular venular flow), in which VCAM-1 ligand interactions induced by TNF-α primarily controlled adherence, to 0.1 dyne/cm2(low flow), in which stimulation had little effect on adherence. At shear stresses analogous to in vivo velocities from laser Doppler ultrasound studies (0.8 and 0.6 dyne/cm2), TNF-α promoted 1.9- and 2.7-fold increases in adhesion compared with unstimulated (baseline) adherence. These findings suggest a dynamic vasoocclusive process that depends on both receptor expression and shear stress. These results indicate that, in the microvasculature, slightly reduced inflow rate, increased receptor expression, or both may result in large increases in sickle erythrocyte adhesion.