The protease produced by Vibrio vulnifrcus enhances vascular permeability through histamine release from mast cells and activation of the plasma kallikrein-kinin system which generates bradykinin when injected into the dorsal skin. V. vulnificus living cells also enhanced vascular permeability within a few hours after the injection into the dorsal skin. The permeability-enhancing activity of living cells was greatly reduced by addition of soybean trypsin inhibitor, a specific inhibitor for plasma kallikrein-kinin system, or anti-protease IgG. Two protease-deficient mutants induced by nitrosoguanidine treatment had only one-tenth permeability-enhancing activity of a wild-type strain. These results indicate that V. vulnificus elaborates the protease in vivo and that the protease elaborated enhances vascular permeability through release of chemical mediators such as histamine and bradykinin and forms edema.