Left ventricular (LV) remodeling after myocardial infarction (MI) is a major cause of subsequent heart failure and death. Recently, we have shown that C-type natriuretic peptide (CNP) was synthesized in cardiac fibroblasts and inhibited both DNA and collagen synthesis of cardiac fibroblasts more potently than atrial and brain natriuretic peptides (ANP and BNP) in vitro. In the present study, we assessed the hypothesis that the in vivo administration of CNP might attenuate cardiac late remodeling post MI. Experimental MI was induced by coronary ligation in male SD rats. CNP at 0.1μg/kg/min (MI+CNP, n=34) or vehicle (MI+vehicle, n=35) were intravenously infused by osmotic mini-pump for 2 weeks from 4 days after MI. LV end-diastolic dimension determined by echocardiography was greater in MI+vehicle than in sham operation (n=34). The LV enlargement was attenuated by CNP infusion (MI+vehicle; 8.3±0.1mm vs MI+CNP; 7.7±0.1mm, p<0.01). LV end-diastolic pressure was higher, and +dP/dt, -dP/dt, and cardiac output were lower in MI+vehicle than in sham. The systolic and diastolic LV dysfunction was significantly improved by CNP, although aortic pressure was not affected. CNP infusion prevented an increase in heart weight to body weight ratio. In addition, CNP significantly attenuated an increase in morphometrical collagen volume fraction in the non-infarct region (Sham; 3.1±0.2%, MI+vehicle; 5.7±0.5%, MI+CNP; 3.9±0.3%), without affecting the infarct size. Furthermore, CNP significantly improved capillary density in the non-infarct region (Sham; 2151±64/mm², MI+vehicle; 1599±69/mm², MI+CNP; 1902±73/mm²). The increases of collagen 1, collagen 3, ANP, and ß-MHC mRNA levels in the non-infarct region were suppressed by CNP. In conclusion, continuous administration of CNP improved LV dysfunction and attenuated the development of cardiac remodeling after MI. Because CNP has much weaker vasorelaxant and natriuretic activities than ANP and BNP, these beneficial effects of CNP might be mediated by direct inhibition of collagen synthesis and acceleration of angiogenesis in the non-infarct region, suggesting the potential usefulness of CNP as a new cardioprotective agent.