Of the several families of adhesion receptors involved in leukocyte-endothelial cell interactions, only the selectins have been shown to initiate leukocyte interaction under physiologic shear; indeed, p2 (CD18) integrins responsible for neutrophil arrest are unable to engage without prior selectin-mediated rolling. In contrast,(~ 4 (CD49d) integrins are shown here to initiate lymphocyte contact (" tethering") in vitro under shear and in the absence of a selectin contribution. The e4 integrin ligands MAdCAM-1 and VCAM-1 support loose reversible interactions including rolling, as well as rapid sticking and arrest that is favored following integrin activation. Moreover, a41~ 7 mediates L-selectin (CD62L)-independent attachment of blood-borne lymphocytes to lamina propria venules in situ. Scanning electron microscopy of e4p7 h~ lymphoid cells reveals that, like L-selectin, a4p7 is highly concentrated on microvillous sites of initial cellular contact, whereas the J~ 2 integrin LFA-1 is excluded from villi. Thus, a4 but not p2 integrins can initiate leukocyte adhesion under flow, a capacity that may be in part a function of topographic presentation on microvilli.