Vibrio vulnificus, an opportunistic human pathogen causing wound infection and septicemia, produces a metalloprotease (VVP) which is suspected to be a virulent determinant. The interactions of VVP, as well as its derivative (PEG1-VVP) modified with polyethylene glycol, with a variety of human plasma proteins were investigated. We found that native VVP and its derivative were able to act directly on many biologically important human plasma proteins even in the presence of alpha-macroglobulin, the sole plasma inhibitor of native VVP. The activities of both classical and alternative pathways of the complement cascade system were drastically abolished by incubation with either VVP. Furthermore, these proteases rapidly digested the A alpha-chain of human fibrinogen into fragment(s) with no clotting ability. Therefore both VVPs are thought to function as a fibrinogenolytic enzyme, causing delay of the coagulation reaction. VVP and PEG1-VVP were also shown to destroy plasma proteinase inhibitors including alpha 1-proteinase inhibitor, a major inhibitor in human plasma. Because endogenous proteolytic enzymes and their inhibitors are indispensable in maintaining physiological homeostasis, these findings suggest that VVP (and PEG1-VVP) may cause an imbalance of human plasma proteinase-proteinase inhibitor systems, thus eliciting an immunocompromised state in the host and facilitating the development of a systemic V. vulnificus infection such as septicemia.