The extracellular metalloendopeptidase (EC 3.4.24.30; coccolysin) from Enterococcus faecalis (Strain OG1-10) inactivates human endothelin-1 by hydrolyzing the peptide primarily at the Ser5-Leu6 and the His16-Leu17 bonds and the human big endothelin at several bonds involving hydrophobic amino acid residues. The big endothelin fragment 22-38 was also hydrolyzed at a high rate. The degradation of endothelin by coccolysin resembles the peptidolytic processing of endothelin by thermolysin. Because E. faecalis is associated with a large number of infectious diseases, it is possible that the manifestation of inflammatory conditions in the presence of this organism is related to the coccolysin-catalyzed inactivation of endothelin.