It is well known that hypoxia, acting mainly through peripheral chemoreceptors, is an important ventilatory stimulus. It is also known that under certain circumstances hypoxia can lead to ventilatory depression, perhaps through its effect on the central nervous system. This study, utilizing dogs, was carried out to determine the degree of hypoxia required to produce ventilatory depression and to study the effects of chloralose anesthesia, variations in blood carbon dioxide tension, and peripheral chemoreceptor denervation on hypoxic ventilatory depression. In the awake, intact dog, ventilatory depression did not occur until the Pao2 = 18.6 plus or minus 0.8 mmHg (SEM). This value was not significantly different from that observed in chloralose anesthetized dogs, Pao2 = 18.7 plus or minus 0.43 mmHg. Hyper- and hypocapnia had no significant effect on the Pao2 at which ventilatory depression occurred. Denervation of either aortic or carotid chemoreceptors produced a very small change in the Pao2 of ventilatory depression, increasing it from 18.6 plus or minus 0.58 to 20.8 plus or minus 0.93 mmHg. Denervation of both aortic and carotid chemoreceptors produced a further small increase (Pao2 = 21.8 plus or minus 0.76 mm Hg). In peripheral chemoreceptor-denervated animals, hypoxia produced no significant change in ventilation until the ventilatory depression point was reached. These studies indicate that in the dog hypoxic ventilatory depression occurs only during severe hypoxia and ventilatory depression occurs only during severe hypoxia and is uninfluenced by chloralose anesthesia, hyper- or hypocapnia, and only slightly affected by chemoreceptor denervation.