The Epidermal Growth factor receptor (EGFR) is a receptor tyrosine kinase involved in the regulation of cell proliferation, survival and differentiation. Pathophysiological effects of EGFR include cell transformation and tumorigenesis as well as parainflammatory dysregulation of tissue homeostasis leading to cardiovascular dysfunction and fibrosis. To investigate the importance of EGFR in VSMC and CM we generated a mouse model with targeted deletion of the EGFR (EGFR^D/DVSMC&CM) using EGFR^flox/floxand SM22-CRE^+/- animals. Deletion of EGFR in VSMC and CM was confirmed by qPCR and EGF-responsiveness of the cells. Litter number and size of EGFR^D/DVSMC&CM is not different from SM22-CRE^+/-. However, lifespan of EGFR^D/DVSMC&CM animals is significantly reduced. Male EGFR^D/DVSMC&CM mice show an 3.5fold increase in heart weight (normalised to tibia length), while female animals show a 2fold increase. Systolic blood pressure and heart rate are not different between the two genotypes but diastolic blood pressure was reduced in knockout animals. Cardiac hypertrophy is accompanied by a significant increase in cardiomyocyte diameter, but not by signs of cardiac fibrosis. Also inflammatory markers were not different between the two genotypes. Left ventricular wall thickness and lumen are increased. Gene expression analysis of aortae showed no signs of fibrosis or inflammation. Our results suggest that loss of CM-EGFR leads to a cardiac hypertrophy possibly resulting in fatal arrhythmias, whereas loss of VSMC-EGFR does not result in an overt vascular phenotype under basal conditions. Thus, although EGFR may serve as a heterologous tansducer of adverse cardiovascular stimuli it is also required for basal tissue homeostasis.