Background Corin is a transmembrane protease that activates ANP and BNP (atrial and B-type natriuretic peptides). Impaired corin expression and function are associated with heart failure. In this study, we characterized a soluble form of corin (sCorin) and examined its effects on cardiac morphology and function in mouse heart failure models. Methods and Results sCorin, consisting of the full-length extracellular fragment of human corin with an engineered activation site, was expressed in Chinese hamster ovary cells, purified from the conditioned medium with affinity chromatography, and characterized in pro-ANP processing assays in vitro and pharmacokinetic studies in mice. Effects of sCorin on mouse models of heart failure induced by left coronary artery ligation and transverse aortic constriction were assessed by ELISA analysis of plasma markers, histologic examination, and echocardiography. We showed that purified and activated sCorin converted pro-ANP to ANP that stimulated cGMP production in cultured cells. In mice, intravenously and intraperitoneally administered sCorin had plasma half-lives of 3.5±0.1 and 8.3±0.3 hour, respectively. In the mouse heart failure models, intraperitoneal injection of sCorin increased plasma ANP, BNP, and cGMP levels; lowered plasma levels of NT-proANP (N-terminal-pro-ANP), angiotensin II, and aldosterone; reduced cardiac hypertrophy and fibrosis; and improved cardiac function. Conclusions We show that sCorin treatment enhanced natriuretic peptide processing and activity, suppressed the renin-angiotensin-aldosterone system, and improved cardiac morphology and function in mice with failing hearts.