C1-inhibitor is the only known inhibitor of the classical pathway of complement and the major inhibitor of the contact pathway of coagulation. Like other serine proteinase inhibitors, C1-inhibitor can exist in three conformations, ie, the native, the proteinase-complexed, and the proteolytically inactivated form. Here we studied the plasma elimination kinetics of these three forms of human C1-inhibitor in rats. The clearance of the complexed form of C1-inhibitor appeared to be the most rapid and depended in part on the proteinase involved (observed plasma t1/2 was 20 minutes for C1s-C1-inhibitor, 32 minutes for kallikrein-C1-inhibitor, and 47 minutes for beta XIIa-C1- inhibitor), whereas that of native C1-inhibitor was the slowest (observed plasma t1/2 4.5 hours). Inactivated C1-inhibitor was cleared with an apparent plasma t1/2 of 1.6 hours. Thus, the short plasma t1/2 of complexed relative to native C1-inhibitor explains why in patients only low concentrations of C1-inhibitor complexes may be observed despite activation of the contact and/or complement systems.