Objective Activation of Fas signaling has been associated with the development of cardiomyocyte hypertrophy. In the present study, we investigated the effects of increased expression of c-Flip, a natural modulator of Fas receptor signaling, in a mouse model of cardiac growth response to pressure overload. Methods A transgenic mouse overexpressing c-Flip in the heart was generated in FVB/N strain. Echocardiographic, hemodynamic, histological and molecular analyses were carried out under basal conditions and after transverse aortic constriction (TAC)-induced pressure overload. Results Overexpression of c-Flip in ventricular heart tissue was functionally silent under basal conditions affecting neither cardiac morphology nor basal cardiac function. Transgenic mice were then subjected to pressure overload by TAC procedure. Under such conditions, c-Flip transgenic mice showed normal left ventricular function with a significantly reduced left ventricular hypertrophy compared with wild-type mice and reduced induction of the cardiac ‘‘fetal’’ gene programme. Further, analysis of intracellular signaling pathways indicated that c-Flip overexpression reduced phosphorylation of both the glycogen synthase kinase 3b (GSK3b) and Akt as compared with controls. Finally, the reduction of the TAC-induced hypertrophy was not accompanied by significant apoptosis increase. Conclusion Altogether, these findings indicate c-Flip as a key regulator of the cardiac response to ventricular pressure overload. J Hypertens 26:1008–1016 Q 2008