Background: Cardiac hypertrophy involves growth responses to a variety of stimuli triggered by increased hemodynamic workload. It is an independent risk factor for heart failure and sudden cardiac death. Estrogen-related receptor gamma (ERR款) is an orphan nuclear receptor lacking identified natural ligand. Its role in the cardiac hypertrophy, however, has not been elucidated yet. Thus, we tried to evaluated the role of ERR款 in the development of cardiac hypertrophy. Methods and Results: We found that cardiac hypertrophy stimuli such as aortic banding and continuous infusion of either isoproterenol or phenylephrine (PE) induced ERR款 expression, and transient overexpression of ERR款 in cardiomyocytes mimicked cardiac hypertrophy. Interestingly, ERR款 increased the protein amounts of heart-specific factors such as GATA4 or SRF, both of which are known to be prohypertrophic transcription factors. In contrast, knockdown of ERR款 blunted the cardiac hypertrophy induced by either PE or endothelin-1 (ET-1). GSK 5182 compound, an ERR款 inverse agonist, also suppressed hypertrophic markers induced by hypertrophic stimuli. Knockdown of GATA4 blocked ERR款-mediated hypertrophic phenotypes in cardiomyocytes. Conclusions: Taken together, our present results suggest that ERR款 may play an important role of evoking cardiac hypertrophy through the induction of cardiac GATA4. In addition, ERR款 inverse agonist can be potential therapeutic drug for the treatment of cardiac hypertrophy.