Thrombin has a crucial role in cardiac remodeling through protease-activated receptor-1 activation in cardiac fibroblasts and cardiomyocytes. As heparin cofactor II (HCII) inhibits the action of tissue thrombin in the cardiovascular system, it is possible that HCII counteracts the development of cardiac remodeling. We investigated the relationships between plasma HCII activity and surrogate markers of cardiac geometry, including left atrial volume index (LAVI), relative wall thickness (RWT) and left ventricular mass index, and deceleration time (DcT) and the ratio of peak E velocity to early diastolic mitral annulus velocity (E/e' ratio) as surrogate markers of left ventricular diastolic dysfunction measured using echocardiography in 304 Japanese elderly individuals without systolic heart failure (169 men and 135 women; mean age: 65.4 ± 11.8 years). Mean plasma HCII activity in all participants was 95.8 ± 17.0% and there was no difference between the mean plasma HCII activities in males and females. Multiple regression analysis revealed that there were significant inverse relationships between plasma HCII activity and LAVI (coefficient: -0.2302, P<0.001), between HCII activity and RWT (coefficient: -0.0007, P<0.05), between HCII activity and DcT (coefficient: -0.5189, P<0.05) and between HCII activity and E/e' ratio (coefficient: -0.0558, P<0.01). Plasma HCII activity was independently and inversely associated with the development of cardiac remodeling, including cardiac concentric change, left atrial enlargement and left ventricular diastolic dysfunction. These findings suggest that cardiac tissue thrombin inactivation by HCII is a novel therapeutic target for cardiac remodeling and atherosclerosis.