Inflammatory mediators such as the vasoactive and chemotactic factors, which are formed during the activation of serum complement, are extremely potent biologic peptides and are thought to be under the rigid control of specific serum-derived regulators or inactivators, including the anaphylatoxin inactivator (AI) and the chemotactic factor inactivator (CFI). Our understanding of the biologic importance and implication of these regulators in inflammatory reactions is primarily based on in vitro observations, and there is only limited data on their in vivo importance. Previously, alterations in CFI and AI levels were detected in chronic inflammatory disease states, but no data on their activity or role during acute inflammatory reactions have been demonstrated. Here we demonstrate the elevation of serum CFI activity during acute inflammatory reactions in rabbits. Specifically, inflammatory reactions were induced in rabbits by intraperitoneal injections of 0.1% oyster glycogen. Rabbit serum CFI levels rose rapidly over the first 4 hours after glycogen injection, reaching levels 4-8 times higher than the preglycogen serum CFI levels. Additional studies demonstrated that acute elevations of serum CFI levels could also be induced in rabbits by intravenous infusion of activated rabbit serum or C5-derived chemotactic factors. Infusion of saline, albumin, or the synthetic chemotactic peptide f-Met-Leu-Phe did not cause elevation of the serum CFI levels in rabbits. Thus, we take these data to support our hypothesis that 1) CFI is a "hyperacute phase reactant" that is elevated during inflammatory reactions, and 2) that this elevation of serum CFI activity is probably triggered by the appearance of specific C5-derived chemotactic factors within the vasculature. These studies not only provide exciting new insights into the regulatory mechanisms involved in acute inflammatory reactions but suggest that novel approaches to antiinflammatory therapy may be forthcoming.