Migration of T cells into extravascular sites of inflammation is mediated by cell–cell and cell–matrix adhesion receptors, including the hyaluronan‐binding glycoprotein, CD44. The biochemical nature of CD44 variants and the ligand specificity, function and the regulation of activation of CD44 expressed on various cell types have been extensively studied. However, little is still known about the short‐term influence of cytokines and chemokines on the activation of CD44 on human T cells. Therefore, we studied the role of inflammatory mediators in regulating the adhesion of T cells from human peripheral blood to immobilized hyaluronan under static or shear stress conditions. We found that the CD44‐dependent adhesion, under static and shear stress (i.e. relative gradual resistance to flow of 150 and 1500 s⁻¹) conditions, of T cells to hyaluronan requires a T‐cell activation of 2–3 hr and is regulated by the cross‐linking of CD3, cytokines (e.g. interleukin‐2 and tumour necrosis factor‐α), and chemokines (e.g. MIP‐1β, interleukin‐8, and RANTES). This T‐cell adhesion was manifested by polarization, spreading and co‐localization of cell surface CD44 with a rearranged actin cytoskeleton in hyaluronan‐bound T cells. Thus, cytokines and chemokines present in the vicinities of blood vessel walls or present intravascularly in tissues where immune reactions take place, can rapidly activate the CD44 molecules expressed on T cells.