Plasmin incubated with partially purified C[unk] inactivator produced a decrease in inhibitory activity which was related to the time of incubation and to the concentration of plasmin. This effect of plasmin was not influenced by the purity of the inhibitor preparations. Soybean trypsin inhibitor and tosyl arginine methyl ester (TAMe), substances which block the active enzymic center of plasmin, prevented the plasmin-induced inactivation. Double diffusion analysis of the functionally deficient, plasmin-treated C[unk] inactivator using a specific antibody, showed a reaction of identity with the untreated inhibitor. Agarose and acrylamide gel immunoelectrophoresis of a plasmin, inhibitor mixture showed the appearance of an additional precipitin band with immunologic reactivity similar to that of the untreated inhibitor. These results demonstrate that plasmin alters both the functional and immunoelectrophoretic properties of C[unk] inactivator, and that the active proteolytic site of plasmin is necessary for this interaction. Since C[unk] inactivator has been shown to inhibit several different proteolytic enzymes including C[unk], kallikrein, PF/Dil, and plasmin, this investigation provides a theoretical relationship between the fibrinolytic, kallikrein, and complement systems which may have pathophysiologic relevance to various human disease states.