The duration of survival during a hypoxic or ischemic incident can be altered by barbiturate anesthesia. If this effect on the brain results from a reduction in lactic acid production by hypoxia, then a similar protective effect may be produced by altering substrate availability. Six groups of mice were subjected to hypoxia (4 to 5% O2, balance N2) at 30 to 35°C: 1. Hypoglycemia was induced by 2 U insulin injected ip 30 min prior to hypoxia. 2. Ketotic hypoglycemia was induced by fasting 85 to 90 hours prior to hypoxia. 3. Hyperglycemia was induced by iv dextrose. 4. Diabetic-ketotic-hyperglycemia was induced by iv alloxan 5 days prior to hypoxia. 5. One group was given both the insulin and dextrose in the above sequence. 6. In controls, saline was given iv or ip when appropriate. The mean survival time for ketotic-hypoglycemic and diabeticketotic- hyperglycemic mice was significantly higher than control. The mean survival time for the insulinhypoglycemic mice was significantly lower than control. The remaining groups showed no difference from control. The observed improvement in survival time from hypoxia seen in the ketotic animals suggests that during hypoxia, the brain metabolizes ketones selectively and minimizes the production of lactic acid to maintain neuronal viability.