Abstract CFIs have been implicated in the regulation of several inflammatory mediators; consequently, we have evaluated the effects of CFI on neutrophil chemotactic and lysosomal enzyme release responses to C 5-derived chemotaxins. Chemotaxis was measured by directed migration under agarose, LER by glucosaminidase release from cytochalasin B-treated neutrophils, and CFI activity by its inhibition of LER. After inactivation by CFI, C 5-fr lost their ability to stimulate neutrophils, and acquired a new chemotactic inhibitory activity. On gel chromatography, the stimulatory activity of C 5-fr and the inhibitory activity of inactivated C 5-fr eluted as separate peaks with different molecular weights. Effects of CFI on neutrophil responses to C 5-fr, ZAS, and ZAP were adverse and dose-dependent: maximal neutrophil response to C 5-fr decreased in amplitude as CFI levels increased, and a close reciprocal relationship was demonstrated between the endogenous CFI and the chemotactic activities of ZAS (r= −0.833) and ZAP (r= −0.932) in 10 healthy adults. The data suggest that CFI is a potent regulator of neutrophil response to C 5-derived inflammatory mediators.