In chronic heart failure (CHF), the abnormally large ventilatory response to exercise (VE/VCO(2) slope) has 2 conceptual elements: the requirement of restraining arterial partial pressure of carbon dioxide (pCO(2)) from increasing (because of an increased ratio between increased physiologic dead space and tidal volume [VD/VT]) and the depression of arterial pCO(2) 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/VCO(2) 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/VCO(2) slope 36.4). At rest and during exercise, arterial pCO(2) 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/VCO(2) 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/VCO(2) slope was also correlated with arterial pCO(2) (r = -0.75, p <0.001). Despite this, arterial pCO(2) 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/VCO(2) slope was caused by both the high VD/VT ratio and by other mechanisms, as shown by low arterial pCO(2) during exercise. Second, this latter component (depression of arterial pCO(2)) was not related to conventional measures of heart failure severity.