The present study investigated whether the platelet-derived growth factor receptor (PDGFR)-β–mediated mechanisms are involved in the hypoxic ventilatory response through modulating the N-methyl-D-aspartate (NMDA) function. The ventilatory changes during hypoxic challenge (10% O₂, 30 min) were measured plethysmographically in mice selectively lacking the PDGFR-β in neurons (KO mice) and in control wild-type mice (WT mice) before and after blockade of NMDA receptors. In baseline breathing at rest, respiratory rate, tidal volume, and minute ventilation were similar between WT and KO mice. Hypoxia caused an increase of ventilation during the early period of exposure (an initial excitation), followed by a progressive decrease along with the exposure period (a late decline). The initial excitation occurred similarly in KO and WT mice, while the late decline was markedly attenuated in KO mice. Administration of an antagonist of NMDA receptors, dizocilpine (0.3 mg/kg, i.p.) decreased the initial excitation and hastened the late decline of hypoxic ventilatory response. Furthermore, the hypoxic ventilatory response in KO mice was indistinguishable from that in WT mice after blockade of NMDA receptors. The present study suggests that the PDGF-BB/PDGFR-β signal axis contributes to the hypoxic ventilatory response by its inhibitory effect on the NMDA receptor–mediated function.