Adverse remodeling after myocardial infarction (MI) determines the progression of heart failure (HF). Failing hearts are characterized by downregulation of beta adrenergic receptor (AR) signalling in part due to increased ARK1 activity. Our previous studies have shown that the overexpression of the phosphoinositide kinase domain (PIK) of phosphoinositide 3-kinase (PI3K), prevents AR downregulation and enhances adrenergic agonist responsiveness by inhibiting targeting of PI3K to the AR complex. To investigate whether preventing AR downregulation in the heart ameliorates cardiac function post MI, transgenic mice with cardiac specific overexpression of the PIK domain peptide (TgPIK) underwent left coronary artery ligation and were subsequently followed by serial echocardiography at 4, 8, 12, 16, and 20 weeks. Despite having similar infarction sizes, TgPIK mice showed better systolic function, less cardiac dilatation and improved hemodynamic responses to dobutamine compared to littermate controls after MI. To test that displacement of PI3K from the AR complex, but not the total loss of PI3Kis critical for amelioration of cardiac function, mice lacking the PI3K (PI3K-KO) underwent MI and their cardiac function assessed 20 weeks post MI. Serial echocardiographic measurements showed severe reduction in contractile performance in PI3K-KO compared to TgPIK mice. Furthermore, significant AR downregulation and desensitization was only seen in infarcted WT and PI3K-KO mice, and not in TgPIK mice. Together, these results demonstrate that adverse remodeling of the ventricle after MI can be attenuated by a strategy that prevents recruitment of PI3K to the plasma membrane and restores normal AR function.