In chronic heart failure (CHF), the abnormally large ventilatory response to exercise (VE/VCO₂ slope) has 2 conceptual elements: the requirement of restraining arterial partial pressure of carbon dioxide (pCO₂₎ from increasing (because of an increased ratio between increased physiologic dead space and tidal volume [VD/VT]) and the depression of arterial pCO₂ by further increased ventilation, which necessarily implies an important non-carbon dioxide stimulus to ventilation. We aimed to assess the contribution of these 2 factors in determining the elevated VE/VCO₂ slope in CHF. Thirty patients with CHF underwent cardiopulmonary exercise testing (age 65 ± 11 years, left ventricular ejection fraction 34 ± 15%, peak oxygen uptake 15.2 ± 4 ml/kg/min, VE/VCO₂ slope 36.4). At rest and during exercise, arterial pCO₂ was measured and VD was calculated and separated into serial and alveolar components. VD/VT decreased from 0.57 at rest to 0.44 at peak exercise (p <0.01). VE/VCO₂ slope was correlated with peak exercise VD/VT (r = 0.67), the serial VD/VT ratio (r = 0.64), and alveolar VD/VT ratio (r = 0.51) at peak exercise (all p <0.01). VE/VCO₂ slope was also correlated with arterial pCO₂ (r = −0.75, p <0.001). Despite this, arterial pCO₂ was not related to peak oxygen uptake (r = 0.2) or to arterial lactate (r = −0.25) and only weakly to New York Heart Association functional class (F = 3.7). First, the increased VE/VCO₂ slope was caused by both the high VD/VT ratio and by other mechanisms, as shown by low arterial pCO₂ during exercise. Second, this latter component (depression of arterial pCO₂) was not related to conventional measures of heart failure severity.