Wiskott-Aldrich syndrome is characterized by numerous humoral and cellular immune abnormalities including anergy, defective antibody production, and increased immunoglobulin synthesis. To define better the mechanisms of defective cellular immunity in this disorder, lymphoproliferative responses, lymphokine production, and the chemotactic responsiveness of mononuclear leukocytes (MNL) from patients with Wiskott-Aldrich syndrome were quantitated. Peripheral blood lymphocytes from these patients produced normal amounts of a lymphocyte-derived chemotactic factor (LDCF); however, their lymphoproliferative responses were frequently depressed, particularly to antigenic stimuli. In the absence of exogenous antigens or mitogens, lymphocytes from patients with Wiskott-Aldrich syndrome produced significantly more LDCF than unstimulated normal lymphocytes. In fact, this unstimulated LDCF production frequently approached the level produced by normal cells only after antigen or mitogen stimulation. The chemotactic responsiveness of MNL from Wiskott-Aldrich syndrome patients was impaired, particularly in those patients with the highest rates of unstimulated LDCF production. Furthermore, normal MNL chemotactic responsiveness could be impaired by preincubation of these cells in either LDCF or plasma from Wiskott-Aldrich syndrome patients. These observations suggest that the regulation of LDCF synthesis is abnormal in Wiskott-Aldrich syndrome, and that a humoral chemotactic inhibitor, perhaps LDCF, "deactivates" the circulating MNL of patients with this syndrome.