Background - Receptor-mediated activation of myocardial Gq signaling is postulated as a biochemical mechanism transducing pressure-overload hypertrophy. The specific effects of Gq activation on the functional and morphological adaptations to pressure overload are not known. Methods and Results - To determine the effects of intrinsic myocyte Gαq signaling on the left ventricular hypertrophic response to experimental pressure overload, transgenic mice overexpressing Gαq specifically in the heart (Gαq-25) and nontransgenic siblings underwent microsurgical creation of transverse aortic coarctation and the morphometric, functional, and molecular characteristics of these pressure-overloaded hearts were compared at increasing times after surgery. Before aortic banding, isolated Gαq-25 ventricular myocytes exhibited contractile depression (depressed +dl/dt and -dl/dt) and Gαq-25 hearts showed a pattern of fetal gene expression similar to the known characteristics of nontransgenic pressure-overloaded mice. Three weeks after transverse aortic banding, Gαq-25 left ventricles hypertrophied to a similar extent (≃30% increase) as nontransgenic mice. However, whereas nontransgenic mice exhibited concentric left ventricular remodeling with maintained ejection performance (compensated hypertrophy), Gαq-25 left ventricles developed eccentric hypertrophy and ejection performance deteriorated, ultimately resulting in left heart failure (decompensated hypertrophy). The signature hypertrophy-associated progress of fetal cardiac gene expression observed at baseline in Gαq-25 developed after aortic banding of nontransgenic mice but did not significantly change in aortic-banded Gαq-25 mice. Conclusions - Intrinsic cardiac myocyte Gαq activation stimulates fetal gene expression and depresses cardiac myocyte contractility. Superimposition of the hemodynamic stress of pressure overload on Gαq overexpression stimulates a maladaptive form of eccentric hypertrophy that leads to rapid functional decompensation. Therefore Gαq-stimulated cardiac hypertrophy is functionally deleterious and compromises the ability of the heart to adapt to increased mechanical load. This finding supports a reevaluation of accepted concepts regarding the mechanisms for compensation and decompensation in pressure-overload hypertrophy.