Introduction: Diabetic cardiomyopathy (DCMP) is a leading cause of cardiac morbidity and mortality. DCMP is characterized by left ventricular (LV) tissue remodeling and by LV diastolic dysfunction, causing LV filling disturbances. Dipeptidyl peptidase-IV (DPP-IV) is a membrane-bound protease, expressed in cardiac microvascular endothelial cells, responsible for the breakdown of several cardio-active peptides. DPP-IV inhibitors are novel drugs for the treatment of type II diabetes. This study investigates the effects of sitagliptin (SITA), an orally active inhibitor of DPP-IV, on LV structure and function in obese diabetic mice. Results: Obese male type II diabetic mice (Leprdb/db, n=24) were treated with SITA (300 mg/kg/day in drinking water) or vehicle during 8 weeks. SITA impaired more than 85% of serum DPP-IV activity but had no effect on fasting glucose levels. SITA reduced cardiomyocyte size (pConclusion: In obese diabetic mice, in absence of hypoglycaemic effects, DPP-IV inhibition by SITA improves global LV performance and LV compliance. These effects seem at least partially mediated by stimulatory effects of SITA on the myocardial cGMP-PKG pathway and, hence, on the phosphorylation status of titin and the hereto coupled cardiomyocyte stiffness modulus.