The aim of this study was to assess whether arterial chemoreceptors are activated in chronic heart failure and to appreciate whether this activation is related to the degree of cardiac dysfunction. We examined whether administration of pure oxygen for 30 min to 35 patients with chronic heart failure was followed by hemodynamic modifications that would suggest a negative feedback (inactivation) of such chemoregulation. A decrease in heart rate and cardiac output was observed in all patients. The decrease in cardiac output and stroke volume was inversely correlated to the left ventricular ejection fraction. We observed that the lower the left ventricular ejection fraction, the smaller the decrease in heart rate and the greater the increase in systemic vascular resistance. The variation of stroke volume was related to the variation of systemic vascular resistance. In 12 patients, keeping heart rate constant during oxygen inhalation by adequate right atrial pacing prevented the decrease of cardiac output. These results suggest that chemoregulation remains generally effective in chronic heart failure: increase in Pao2 resulted in a reduction of cardiac output mainly related to the decrease of heart rate. However, when the left ventricular function is very poor, the central chemomediated regulation is impaired, and the direct peripheral effect of oxygen on systemic circulation appears to play a leading part.