Inputs from central (brainstem) and peripheral (carotid body) respiratory chemoreceptors are coordinated to protect blood gases against potentially deleterious fluctuations. However, the mathematics of the steady-state interaction between chemoreceptors has been difficult to ascertain. Further, how this interaction affects time-dependent phenomena (in which chemo-responses depend upon previous experience) is largely unknown. To determine how central PCO₂ modulates the response to peripheral chemo-stimulation in the rat, we utilized an in situ arterially perfused, vagotomized, decerebrate preparation in which central and peripheral chemoreceptors are perfused separately (i.e., dual perfused preparation; DPP). We carried out two sets of experiments: Experiment #1, we alternated steady-state brainstem PCO₂ between 25 and 50 Torr in each preparation and applied specific carotid body hypoxia (60 Torr PO₂ and 40 Torr PCO₂) under both conditions; Experiment #2, we applied four 5 min bouts (separated by 5 min) of specific carotid body hypoxia (60 Torr PO₂ and 40 Torr PCO₂) while holding the brainstem at either 30 Torr or 50 Torr PCO₂. We demonstrate that the level of brainstem PCO₂ modulates (a) the magnitude of the phrenic responses to a single step of specific carotid body hypoxia and (b) the magnitude of time-dependent phenomena. We report that the interaction between chemoreceptors is negative (i.e., hypo-additive), whereby a lower brainstem PCO₂ augments phrenic responses resulting from specific carotid body hypoxia. A negative interaction may underlie the pathophysiology of central sleep apnoea in populations that are chronically hypocapnic.