(1) Background: The exercise capacity of patients with a left ventricular assist device (LVAD) remains limited despite mechanical support. Higher dead space ventilation (VD/VT) may be a surrogate for right ventricular to pulmonary artery uncoupling (RV–PA) during cardiopulmonary exercise testing (CPET) to explain persistent exercise limitations. (2) Methods: We investigated 197 patients with heart failure and reduced ejection fraction with (n= 89) and without (HFrEF,n= 108) LVAD. As a primary outcome NTproBNP, CPET, and echocardiographic variables were analyzed for their potential to discriminate between HFrEF and LVAD. As a secondary outcome CPET variables were evaluated for a composite of hospitalization due to worsening heart failure and overall mortality over 22 months. (3) Results: NTproBNP (OR 0.6315, 0.5037–0.7647) and RV function (OR 0.45, 0.34–0.56) discriminated between LVAD and HFrEF. The rise of endtidal CO2(OR 4.25, 1.31–15.81) and VD/VT(OR 1.23, 1.10–1.40) were higher in LVAD patients. Group (OR 2.01, 1.07–3.85), VE/VCO2(OR 1.04, 1.00–1.08), and ventilatory power (OR 0.74, 0.55–0.98) were best associated with rehospitalization and mortality. (4) Conclusions: LVAD patients displayed higher VD/VTcompared to HFrEF. Higher VD/VTas a surrogate for RV–PA uncoupling could be another marker of persistent exercise limitations in LVAD patients.