Heterozygous mutations of the transcription factor PHOX2B have been found in most patients with central congenital hypoventilation syndrome (CCHS), a rare disease characterized by sleep-related hypoventilation and impaired chemosensitivity to sustained hypercapnia and sustained hypoxia. PHOX2B is a master regulator of autonomic reflex pathways, including peripheral chemosensitive pathways. In the present study, we used hyperoxic tests to assess the strength of the peripheral chemoreceptor tonic drive in Phox2b+/- newborn mice. We exposed 69 wild-type and 67 mutant mice to two hyperoxic tests (12 min air followed by 3 min 100% O₂) 2 days after birth. Breathing variables were measured noninvasively using whole-body flow plethysmography. The initial VE decrease was larger in mutant pups than in wild-type pups: -37% (SD 13) and -25% (SD 18), respectively, P<0.0001. Furthermore, VE remained depressed throughout O₂ exposure in mutants, possibly because of their previously reported impaired CO₂ chemosensitivity, whereas it returned rapidly to the normoxic level in wild-type pups. Hyperoxia considerably increased total apnea duration in mutant compared to wild-type pups (P=0.0001). A complementary experiment established that body temperature was not influenced by hyperoxia in either genotype group and therefore did not account for genotype-related differences in the hyperoxic ventilatory response. Thus, partial loss of Phox2b function by heterozygosity did not diminish the tonic drive from peripheral chemoreceptors.