Introduction The transcription factor Phox2b is a master regulator of the noradrenergic phenotype and of dl neuronal relays of the autonomic medullary reflex pathways including peripheral chemoreceptors and their afferent viscerai pathways. Heterozygous mutations of Phox2b have been found in a high proportion of patients with Central Congenitd Hypoventilation Syndrome (CCHS), a rare autosomal dominant syndrome characterized by hypoventilation during sleep, and impaired ventilatory responses to hypercapnia and hypoxia. We previously showed that Phox2b+/- mutant mice showed a blunted response to CO2 [l], and a large increase in sleep apnea total time . However, the hyperpneic response to hypoxia was normd [l]. The aim of this study was to examine chemosensitivity to 0 2 in Phox2B+/- pups using an hyperoxic test. Methods 136 wild-type and mutant two-day old pups were exposed to two hyperoxic tests (12 min air followed by 3 min 02), followed by 12 min air. Breathing variables and apneas were measured noninvasively using whole body flow plethysmography. We evaluated the ventilatory response to hyperoxia based on the maximal VE decline, i.e., the minima VE value (min VE) over the 3 min of O2 exposure expressed as the percentage of the baseline level. Results . Conclusion Sensitivity to O 2 was not impaired in Phox2B+/- newborn pups, in line with previous results showing their normal hyperpneic response to hypoxia, and in contrast with CCHS. However, hyperoxia caused a sustained ventilatory depression in mutant pups, suggesting that disruption of Phox2B impaired activatory processes of breathing. This latter effect may contibute to sleep-related respiratory disorders in CCHS.