Objectives: There is still little information about the cardiorespiratory effects of cardiac resynchronization therapy (CRT) in patients undergoing all-day physical activity. This study aimed to assess the effects of CRT on ventilatory perfusion coupling during submaximal exercise. Methods: Metabolic and hemodynamic parameters were obtained during treadmill exercise testing as well as during rest for each single-right (RV), -left (LV) and biventricular (BiV) pacing mode as well as during intrinsic conduction (VVI 30) in 37 patients. Only responders to CRT (>10% increase in cardiac output (CO) during BiV pacing; n = 27) were included into the evaluation. Results: LV and BiV pacing increased systolic (144 ± 25 and 142 ± 28 vs. 118 ± 29 mm Hg, p < 0.05) and mean blood pressure (108 ± 19 and 109 ± 19 vs. 94 ± 25 mm Hg, p < 0.05) as well as CO (7.0 ± 0.6 and 7.2 ± 0.8 vs. 6.0 ± 0.6 l/min, p < 0.05 and p < 0.01) during exercise as compared to VVI 30. Simultaneously, LV and BiV pacing decreased dead space ventilation (18 ± 3 and 17 ± 3 vs. 20 ± 4, p < 0.01) and the ventilatory equivalent for oxygen (31 ± 4 and 31 ± 5 vs. 36 ± 6; p < 0.05) compared to intrinsic conduction. Conclusion: The improvement in ventilatory efficacy during CRT, which is demonstrated by the decrease in the ventilatory equivalent for oxygen, results from an increase in CO and thus from a reduction in the ventilatory perfusion mismatch.