Variation in the human glucocorticoid receptor (GR) gene associates with relative glucocorticoid resistance, hypertension and increased cardiovascular disease risk. Here, the contribution of cardiac GR to disease risk was assessed in male and female “SMGRKO” mice with cardiomyocyte and vascular smooth muscle deletion of GR. SMGRKO mice, generated from GR “floxed” (congenic on C57BL/6J) x SM22α-Cre crosses, have reduced cardiac GR protein and mRNA levels (by 52% and 57%, respectively), compared to Cre-negative littermate controls. Interestingly, fewer female SMGKRO mice survive to weaning [SMGRKO: Control; females 23:68(25%); males 42:52(45%)]. Doppler measurements (Visual Sonics Vevo770 ultrasound) of blood flow within the left ventricle show a detrimental increase in the myocardial performance index, which represents combined systolic and diastolic function, in both sexes of adult SMGRKO mice, primarily due to greater isovolumetric contraction time (p < 0.05) indicating impairment of the initial left ventricular contractile phase. In males only, cardiomyocyte size and heart weight (% body weight) are increased (Control: 0.5 ± 0.02%; SMGRKO: 0.55 ± 0.01%, p < 0.05), as are levels of mRNA encoding myosin heavy chain-β, a marker of pathological cardiac hypertrophy (p < 0.05). Both sexes showed left ventricular fibrosis (histopathology) and elevated levels of mRNA encoding pro-fibrotic factors. Thus, cardiomyocyte/smooth muscle GR-deficiency causes the same functional impairment of isovolumetric contraction but differential pathological changes in the left ventricle of male and surviving female mice. Whether pathology is worse in females that died before weaning is under investigation. Nevertheless, these findings support a role for cardiomyocyte GR in determination of cardiovascular disease risk, though without overt signs of cardiac hypertrophy in females.