Aims: Multiple factors lead to the development and maintenance of chronic heart failure. Blockade of ErbB-2 or ErbB-4 tyrosine kinase receptor signaling leads to dilated cardiomyopathy. ErbB-1 may protect the heart against stress-induced injury and its ligand, epidermal growth factor (EGF) increases myocardial contractility while heparin-binding EGF is essential for normal cardiac function. However, the role of ErbB-1 in control of cardiac function is not clear. We hypothesized that ErbB-1 is essential for maintaining adult cardiac function. Methods: Using ecdysone inducible gene expression system, we expressed cardiomyocyte-specific dominant-negative ErbB-1 mutant receptors (hErbB-1-mut) in young adult mice that block endogenous cardiac ErbB-1 signaling. Molecular, morphological and physiological tests (under anesthesia) were performed. Results: hErbB-1-mut was expressed selectively in cardiomyocytes leading to blockade of endogenous ErbB-1 phosphorylation and ErbB-2 transphosphorylation. Increase in left ventricular mass, atrial natriuretic factor expression and histological changes were indicative of cardiac hypertrophy. Cardiac dilation, numerous cardiac lesions and loss of clear boundary between cardiac fibrils were noted histologically. Early and long-term hErbB-1-mut induction led to significant decrease in fractional shortening, and significant increases in left ventricular end-systolic diameter and volume. Treatment of adenylyl cyclase activator (forskolin analogue) normalized the depressed cardiac function. Resting cardiac function returned to normal after reversing mutant expression. Four-day survival rate of transverse-aortic constricted hErbB-1-mut mice was only 20% compared to 100% in controls. Conclusion: These observations indicate that blockade of cardiac ErbB-1 signaling leads to blockade of ErbB-2 signaling and together they result in cardiac dysfunction.