Cutaneous lymphocyte antigen (CLA) has been reported to be expressed mainly by memory/effector T lymphocytes infiltrating inflammatory skin lesions and cutaneous T-cell lymphoma. It has been suggested that CLA is a specific homing receptor, facilitating the T-cell migration into skin lesions, and also an indicator of the skin-homing T-cell subset. In the present study, we investigated the expression of CLA in natural killer (NK) cells defined phenotypically as surface CD3- and CD56+ cells in peripheral blood. CLA was definitely expressed on CD3-CD56+ cells at a level comparable to CD3+ cells in peripheral blood of normal Japanese volunteers. After in vitro stimulation of peripheral blood mononuclear cells with interleukin 2 (IL-2) and IL-12, there was a significant increase in the number and percentage of CLA+ NK cells but not CLA+ T cells (P < 0.01). To analyse the characteristics of CLA expressed by NK cells, we investigated a CLA+ NK-leukaemia cell line, NK-YS, established from a patient with NK leukaemia/lymphoma with skin infiltration. In the in vitro study, the CLA-expressing NK-leukaemic cell line bound to E-selectin-transfected cells and was inhibited by HECA 452 antibody or neuraminidase treatment of leukaemic cells. These findings suggest that CLA expressed by NK cells is a homing receptor for the E-selectin molecule and may explain skin infiltration by NK cells and NK lymphoma cells analogous to T cells. An NK-cell subset expressing CLA must play an important role in host defence against microorganisms and neoplasms in skin lesions.