The potential role of integrins in the epidermotropism of the atypical lymphocytes of Sézary syndrome was studied by monitoring the expression of alpha and beta chains and their major ligands in skin biopsies and peripheral blood cells in patients at different progression stages. Most mononuclear cell integrins were also detected on infiltrating cells including the leukocyte complex CD11/CD18, alpha 4 beta 1, and their ligands, ICAM-1 and VCAM-1. Conversely, alpha 6 and beta 4 were present only in epidermal basal cells. Mononuclear infiltrates of SS were positive for both alpha 3 and alpha 5 chains, whereas in inflammatory cutaneous diseases only alpha 5 was expressed, indicating that a major feature of Sézary cells is the unique expression of alpha 3 beta 1. Significant changes of alpha 3 beta 1 were monitored in the follow-up of Sézary patients and correlated with the results of the therapy. The heterodimer alpha 1 beta 1 was absent from mononuclear cells except in one case. Among matrix molecules, laminin and type IV collagen displayed a pattern similar to that of the controls, whereas fibronectin and tenascin deposition were apparently increased. Circulating Sézary cells, both at diagnosis and during follow-up, were alpha 3 and alpha 5 negative and failed to acquire these adhesion molecules after mitogenic stimulation. We propose that the expression of alpha 3 beta 1 is a distinguishing feature of skin-infiltrating Sézary cells and may be related to their epidermotropism. It could also be adopted as an additional parameter of the progression and therapeutic stage of Sézary syndrome.