In the course of examining polymorphonuclear leukocyte (PMN) chemotaxis in patients with systemic lupus erythematosus (SLE), we have found a previously undescribed serum “inhibitor” of complement (C5)-derived chemotactic activity. Serum from a 25-year-old Black female with untreated SLE, when activated with zymosan, failed completely to attract either her own or normal PMN (measured by the “leading front” method of Zigmond and Hirsch). Incubation of normal PMN with the patient's serum (PS) did not affect random motility or chemotaxis towards normal zymosan-treated serum (ZTS). Whereas levels of C3 were modestly low in PS, no gross abnormalities involving alternative complement pathway activation could be detected. Furthermore, treatment of PS with zymosan resulted in the generation of normal amounts of C5-derived PMN lysosomal enzyme releasing activity (attributable to “C5a”). Incubation of normal ZTS or column (Sephadex G-75)-purified “C5a” with PS did not affect lysosomal enzyme releasing activity but did result in a significant dose-dependent diminution of chemotactic activity.