I diopathic-dilated cardiomyopathy (IDC) is a common primary myocardial disease of unknown etiology characterized by progressive biventricular failure, cardiac dilatation, and premature mortality. Here we show that transgenic mice expressing a dominant-negative form of the CREB transcription factor (CREBA133) under the control of the cardiac myocyte-specific alpha-MHC promoter develop dilated cardiomyopathy that closely resembles many of the anatomical, physiological, and clinical features of human IDC. Between 2 and 20 wk of age, these mice develop four chamber cardiac dilatation, decreased systolic and diastolic left ventricular function, and attenuated contractile responses to the beta-adrenergic agonist, isoproterenol. Histologically, the CREBA133 hearts demonstrated both atrophic and hypertrophied fibers as well as significant interstitial fibrosis. These anatomical and hemodynamic changes were associated with hepatic congestion and peripheral edema, intracardiac thrombi, and premature mortality. Taken together, these results implicate CREB as an important regulator of cardiac myocyte function and provide a genetic model of dilated cardiomyopathy which should facilitate studies of both the pathogenesis and therapy of this clinically important disorder.