The recent characterization of the cutaneous lymphocyte-associated antigen (CLA) as a skin-selective homing receptor for skin-associated memory T cells has suggested a possible mechanism for the tropism demonstrated by the neoplastic T cells in cutaneous T-cell lymphoma (CTCL). In this study, we used five parameter flow cytometry to evaluate expression of CLA and the peripheral lymph node homing receptor L-selectin on circulating T cells in a series of patients with CTCL. Because CTCL cells were previously shown to be CD7-, we looked at expression of these receptors on the CD7- T-cell subset as well as on total T cells. Our results indicate that CTCL patients have increased levels of both CLA+ and CD7- cells in their peripheral blood and that these abnormalities are not seen in patients with other cutaneous disorders. The levels of the CLA-bearing subset correlated with extent of cutaneous but not lymph node disease. By contrast, the CD7- L-selectin+ subset correlated with peripheral lymph node involvement by CTCL. Only the CD7- L-selectin- subset correlated with the number of morphologically abnormal lymphocytes in the peripheral blood. The results support the hypothesis that expression of tissue-selective homing receptors contributes to the unique pattern of tissue involvement seen in patients with CTCL.