To assess the ability of the sarcoidal granuloma to modify peripheral mononuclear cell function, we assayed the culture supernatants of cutaneous granulomata for modulators of monocyte locomotion. The supernatants of granulomata from each of 11 patients contained a cell-directed inhibitor of monocyte leukotaxis. No inhibitory activity was detected in the supernatants of histologically normal skin biopsies. The inhibitor acted only on monocytes, possessed a molecular weight of 230,000 daltons, and was clearly distinct from migration inhibition factor (MIF), leukotactic lymphokines, and immunoglobulins. A physicochemically and functionally indistinguishable inhibitor was present in patient plasma. Production of the inhibitor by the granuloma required active protein synthesis. Culture supernatants also contained MIF and a leukotaxin inactivator. These observations indicate the potential of the sarcoidal granuloma to exert local and, perhaps, systemic regulation of inflammatory processes.