Objective: The 16 kDa adipokine leptin has been shown to exert direct hypertrophic effects on cultured cardiomyocytes although its role as an endogenous contributor to postinfarction remodeling and heart failure has not been determined. We therefore investigated the effect of leptin receptor blockade in vivo on hemodynamic function and cardiac hypertrophy following coronary artery ligation. Methods and results: Cardiac function and biochemical parameters were measured in rats subjected to 7 or 28 days of left main coronary artery ligation (CAL) in the presence and absence of a leptin receptor antibody. Animals subjected to an identical treatment in which the artery was not tied served as sham controls. CAL produced myocardial hypertrophy which was most pronounced 28 days postinfarction as demonstrated by increases in both LVW/BW and ANP gene expression both of which were abrogated by leptin receptor antagonism. Leptin receptor blockade also significantly improved left ventricular systolic function, attenuated the increased left ventricular end diastolic pressure and reduced expression of genes associated with extracellular matrix remodelling 28 days following CAL. Conclusions: The ability of a leptin receptor neutralizing antibody to improve cardiac function offers evidence that endogenous leptin contributes to cardiac hypertrophy following CAL. The possibility exists that targeting the myocardial leptin receptor represents a viable and novel approach towards attenuating postinfarction remodeling.