Background— In patients with left ventricular systolic dysfunction (LVSD), the rate at which oxygen uptake (V O ₂ ) increases on initiation of exercise is inadequate to match metabolic demands. To gain mechanistic insights into delayed V O ₂ kinetics in LVSD, we simultaneously assessed hemodynamic measurements, ventilatory parameters, and peripheral oxygen usage during exercise. Methods and Results— Forty-two patients with symptomatic LVSD (age, 59±2 years [mean±SEM]; LV ejection fraction, 30±1%) and 17 controls (LV ejection fraction, 68±1%) underwent maximum upright cycle ergometry cardiopulmonary exercise testing. Hemodynamic monitoring and first-pass radionuclide ventriculography were performed at rest and during exercise. V O ₂ kinetics were quantified by mean response time (MRT), which was significantly longer in patients with LVSD compared with controls (64±3 versus 45±5 s; P =0.004). In LVSD patients, MRT was associated with higher biventricular filling pressures and reduced cardiac output during early exercise. LVSD patients with MRT ≥60 s, compared with LVSD subjects with MRT <60 s, demonstrated greater impairment in right ventricular-pulmonary vascular function during exercise as evidenced by lower right ventricular ejection fraction (35±2 versus 45±2%; P =0.03), steeper increment in transpulmonary gradient relative to cardiac output (3.7 versus 2.2 mm Hg/L; P <0.001), and increased ventilatory dead-space fraction (17±1 versus 12±2%; P =0.03). In contrast, MRT was not associated with LV ejection fraction (rest, exercise), Pa O ₂ , hemoglobin, or resting pulmonary function test results. Conclusions— Delayed oxygen uptake on initiation of exercise (ie, MRT ≥60 s) in LVSD is closely related to impaired right ventricular-pulmonary vascular function and may represent an important surrogate for inability to augment RV performance during physical activity in patients with heart failure.