Two for the price of one: Full length variegin competitively inhibits thrombin in a substrate-like fashion. Upon proteolysis, the cleaved fragment is able to inhibit thrombin noncompetitively; this results in overall prolonged and potent inhibition. This is the first account of a potent and specific classical noncompetitive inhibitor of the thrombin active site, and is unlike other cleavable substrates or inhibitors of thrombin.