Dilated cardiomyopathy (DC) is a leading cause of cardiovascular morbidity, and nonpharmacological therapies, such as exercise training, have been suggested. The effects of exercise on left ventricular (LV) function and mortality remain controversial. Using a recently described murine model of DC, which involves a dominant-negative form of the cAMP response element binding protein (CREB) transcription factor (CREB(A133)) under the control of the cardiac myocyte-specific alpha-myosin heavy chain promoter, we sought to assess the effects of moderate-intensity exercise training on LV performance and mortality. Thirty-two transgenic mice were subjected to exercise training and compared with sedentary controls. There was progressive enlargement in LV dimensions in both the sedentary and exercise-trained mice. LV performance was progressively impaired, and exercise training did not prevent this decline. The sedentary CREB(A133) mice displayed a significantly increased rate of death, and exercise training did not prevent or delay this excess mortality. The CREB(A133) murine model of inherited DC demonstrated progressive ventricular dilatation and dysfunction with increased mortality, which was not altered with 12 wk of moderate-intensity exercise training.