<p>Adult mammalian hearts lack the ability to regenerate after a myocardial infarction, which leads to heart failure progression. Therefore, finding ways to promote regeneration is a major goal in the development of cardiovascular therapies. In this study, we focus on the role of Myc moderate overexpression in response to acute ischemic injury. We have previously shown that moderate Myc overexpression is not detrimental to cardiac function and promotes cell competition and a hyperplastic phenotype. Here, we describe that Myc overexpression in non-regenerative postnatal hearts promotes functional improvements and reduced scar formation after myocardial infarction. This response correlates with a hyperplastic phenotype in postnatal and adult hearts, characterized by bigger hearts, smaller cardiomyocyte size and increased BrdU incorporation without ploidy increase. Moreover, we show that Myc strongly enhances diploid cardiomyocyte proliferation and the generation of new binucleated cardiomyocytes. Thus, Myc promotes functional and morphological improvements in the heart following acute ischemia and this response correlates with promotion of hyperplasia versus hypertrophy.</p>