Adhesive interactions between receptors on vascular endothelial cells (EC) and circulating leukocytes are pivotal in regulating leukocyte extravasation. Although primary adhesion of lymphocytes to EC has been primarily attributed to the selectin family of receptors, CD44 can also mediate this function when activated to bind its ligand hyaluronan (HA). Triggering through the T cell receptor induces activated CD44 and CD44‐dependent primary adhesion in both human and mouse lymphocytes, and the interaction can mediate the extravasation of activated T cells into an inflamed site. Lymphocytes capable of CD44/HA‐dependent primary adhesion are found in peripheral blood of some rheumatologic patients, and their presence is associated with concurrent symptomatic or active disease. Thus, circulating T cells bearing activated CD44 may represent a pathogenically important subpopulation of activated cells that is elevated under conditions of chronic inflammation. Together, these data add to the selectin and immunoglobulin gene families a new receptor/ligand pair and further our understanding of their potential physiological role; i.e., antigen‐specific T cell activation together with local vascular inflammation permits the CD44/HA interaction and subsequent T cell extravasation. J. Leukoc. Biol. 66: 315–321; 1999.