When exposed to hypoxia, intact mice, with elevated blood ketones, live longer than mice with normal blood ketones. To evaluate a possible mechanism responsible for this phenomenon a rat brain slice preparation was used to determine if brain tissue would utilize glucose or ketones preferentially during exposure to reduced oxygen. Reducing available oxygen in the incubation medium from 95%, in steps, to 5% produced the expected gradual reduction in the carbon dioxide formation from glucose. In contrast, reducing the oxygen level to 40 and 20% resulted in a statistically significant stimulation of the production of carbon dioxide from the ketone beta-hydroxybutyrate. At very low oxygen levels carbon dioxide production from either substrate was reduced. These results are consistent with the hypothesis that ketones can be used in addition to glucose as a substrate for brain energy production even during reduced oxygen availability. If the increase in carbon dioxide production from ketones can be equated with an increase in energy production from this supplemental substrate then ketones may be therapeutically useful in avoiding the collapse of brain function during moderate hypoxia.