The interaction of red blood cells (RBCs) with vascular endothelium under flow conditions was investigated using the perfused rat mesocecum. Under videomicroscopy, normal human erythrocytes were found to adhere to the venular endothelium of desmopressin-treated microvasculature. Transmission electron microscopy showed that the erythrocytes were attached to the endothelial cells at discrete electron-dense sites. Compared with control preparations in which the microvasculature was perfused with Ringer's-albumin solution alone, more than a 10-fold increase in radioactivity was retained in the desmopressin-treated microvasculature when technetium (99mTc)-labeled erythrocytes were infused into the vasculature. This erythrocyte adherence was accompanied by a higher increment in vascular resistance during the passage of RBCs through the microcirculation, and by a delay in the recovery toward baseline. The erythrocyte adherence in desmopressin-treated microvasculature was completely abolished with antibodies to von Willebrand factor (vWF). Desmopressin infusion in rats resulted in elevated vWF antigen levels and the appearance of extra-large molecular weight forms of vWF in plasma. These findings suggest that normal erythrocytes adhere to desmopressin-conditioned microvascular endothelium and that endothelial cell-derived vWF is involved in the erythrocyte-endothelium interaction.