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 chemoresponses depend upon previous experience) is largely unknown. To determine how central PCO2 modulates the response to peripheral chemostimulation in the rat, we utilized an in situ arterially perfused, vagotomized, decerebrate preparation, in which central and peripheral chemoreceptors were perfused separately (i.e. dual perfused preparation (DPP)). We carried out two sets of experiments: in 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; in 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.