The oxygen supply to the retina in man and most mammals is derived from both the retinal and choroidal circulations. However, some mammals have only a partially vascularized retina, and some have a completely avascular retina. Here we contrast the retinal oxygen levels during systemic hyperoxia in a fully vascularized retina (rat), a partially vascularized retina (rabbit), and an avascular retina (guinea pig). Oxygen sensitive microelectrodes were used to measure the intraretinal oxygen distribution in anaesthetized rats, rabbits and guinea pigs during air breathing and 100% oxygen ventilation. In the vascularized rat retina the increase in oxygen tension in the choroid, reflected the increase in systemic oxygen levels during hyperoxic ventilation. However, the rise in oxygen levels in the inner retina was muted. In the avascular region of the partially vascularized rabbit retina, the increase in choroidal oxygen tension resulted in a large increase in oxygen tension across the full thickness of the retina. In the avascular retina of the guinea pig, very little change in choroidal or retinal oxygen tension was seen during systemic hyperoxia. Remarkably different responses to systemic hyperoxia are evident in the rat, rabbit, and guinea pig, three conventional laboratory animals that are commonly used in ophthalmic research. Neither the regulatory mechanisms responsible for the increase in oxygen consumption in the rat retina, or the stability of the choroidal oxygen tension in the guinea pig during systemic hyperoxia are currently understood. A better understanding of oxygen regulation in the mammalian retina could open up new avenues for improving the oxygen environment in the human retina in a range of ischaemic retinal diseases that account for the majority of blindness in the developed world.