A granulocyte release-promoting activity (RPA) has been identified in serum from a patient with chronic pruritus. Secretion from granulocytes of both primary granule components (myeloperoxidase) and secondary granule components (lactoferrin) as well as of eosinophil granule components (eosinophil cationic protein) was induced in suspension. Secretion was non-cytotoxic and fast with approximately 70% of the maximum amount secreted after 1 min. RPA has a molecular size of about 10,000 as judged from ultrafiltration and gel filtration studies. In vivo activity of RPA was evidenced by the very high levels of lactoferrin and eosinophil cationic protein (ECP) in serum in spite of unaltered numbers of blood cells, and paralleled and reduced contents of these proteins within the isolated granulocytes. The symptoms of the patient and the serum levels of the granulocyte proteins have shown a rough correlation of high levels with severe symptoms. Pruritus could be induced by local water challenge of the skin. Simultaneous systemic or local blood sampling under such conditions showed a quick rise in serum lactoferrin paralleled by a rise in RPA as tested in vitro with normal cells. No change in blood histamine or histamine metabolite excretion was observed. The release promoting activity as demonstrated in this report seems to promote secretion of granulocyte proteins in the absence of simultaneous membrane perturbation and may therefore be a demonstration of a distinct and unrecognized pathway of triggering granulocyte secretion.