Human C1̄-INH is a 4S neuraminoglycoprotein in normal serum that complexes stoichiometrically with and thereby inhibits the enzymatic activities of C1̄s, C1̄r, kallikrein, plasmin, activated Hageman factor, anaphylatoxin inactivator. Inherited deficiency of C1̄-INH activity has been associated with the clinical syndrome of hereditary angioneurotic edema. In this study, the effect of the enzymatic removal of sialic acid from C1̄-INH on its functional activity and metabolic behavior was evaluated. C1̄-INH was isolated from normal human plasma by column chromatography and preparative polyacrylamide gel electrophoresis. The highly purified protein was shown by SDS polyacrylamide gel electrophoresis to be comprised of a single polypeptide chain, m.w. 90,000. Incubation of C1̄-INH, at pH 7.4 with Vibrio cholerae neuraminidase at a ratio of 10:1 (wt/unit) for 60 min at 37°C resulted in the release of about 12% of the total sialic acid content. This treatment did not result in any gross alteration of the structure of C1̄-INH as assessed by its antigenicity, m.w. and C1̄s inhibitory activity.