The assessment of myocardial work (MW) by pressure-strain loops is a recently introduced tool for the assessment of myocardial performance. Aim of the present study is to evaluate the relationship between myocardial work and exercise tolerance in patients with dilated cardiomyopathy (DCM). 51 patients with DCM (mean age 57 ± 13 years, left ventricular ejection fraction: 32 ± 9%) underwent cardiopulmonary exercise test (CPET) to assess exercise performance. 22 patients (43%) had left or right bundle branch block with QRS duration > 120 ms. Trans-thoracic echocardiography (TTE) was performed before CPET. The following indices of myocardial work (MW) were measured regionally and globally: constructive work (CW), wasted work (WW), and work efficiency (WE). Left ventricular dyssynchrony (LV-DYS) was defined by the presence of septal flash or apical rocking at TTE. LV-DYS was observed in 16 (31%) patients and associated with lower LV ejection fraction (LVEF), lower global and septal WE, and higher global and septal WW. In patients with LV-DYS, septal WE was the only predictor of exercise capacity at multivariable analysis (β = 0.68, p = 0.03), whereas LVEF (β = 0.47, p = 0.05) and age (β = - 0.42, p = 0.04) were predictors of exercise capacity in patients without LV-DYS. In patients with DCM, LV-DYS is associated with an heterogeneous distribution of myocardial work. Septal WE is the best predictor of exercise performance in these patients.