We assessed the contribution of carotid body chemoreceptors to the ventilatory response to specific CNS hypercapnia in eight unanaesthetized, awake dogs. We denervated one carotid body (CB) and used extracorporeal blood perfusion of the reversibly isolated remaining CB to maintain normal CB blood gases (normoxic, normocapnic perfusate), to inhibit (hyperoxic, hypocapnic perfusate) or to stimulate (hypoxic, normocapnic perfusate) the CB chemoreflex, while the systemic circulation, and therefore the CNS and central chemoreceptors, were exposed consecutively to four progressive levels of systemic arterial hypercapnia via increased fractional inspired CO(2) for 7 min at each level. Neither unilateral CB denervation nor CB perfusion, per se, affected breathing. Relative to CB control conditions (normoxic, normocapnic perfusion), we found that CB chemoreflex inhibition decreased the slope of the ventilatory response to CNS hypercapnia in all dogs to an average of 19% of control values (range 0-38%; n = 6), whereas CB chemoreflex stimulation increased the slope of the ventilatory response to CNS hypercapnia in all dogs to an average of 223% of control values (range 204-235%; n = 4). We conclude that the gain of the CNS CO(2)/H(+) chemoreceptors in dogs is critically dependent on CB afferent activity and that CNS-CB interaction results in hyperadditive ventilatory responses to central hypercapnia.