The aim of the present study was to evaluate whether lactate can maintain the energy metabolism and electrical activity of isolated perfused rat brain in the absence of glucose. To exhaust cerebral glucose stores and simultaneously raise endogenous lactate, complete ischemia was induced. After ischemia, when a glucose-free perfusate was supplied, restoration of interstitial potassium (Ke+), cortical discontinuous current (DC) potential, electroencephalogram (EEG) activity, and ATP and phosphocreatine (PCr) was not significantly different from postischemic recovery findings when a glucose-containing perfusate was used. In the group receiving glucose-free perfusate, postischemic application of 1 mM iodoacetic acid did not inhibit the recovery of electrical activity, Ke+, or DC potential. After recovery of Ke+ in glucose-free reperfusion, a 20-30-Hz EEG pattern appeared and was maintained for about 20 min followed by disappearance of spontaneous electrical activity. An abrupt increase of Ke+, a steep negative DC shift, and a substantial decrease of ATP and PCr occurred after about 22 min of reperfusion. During the first 5 min of glucose-free reperfusion, consumption of lactate was significantly higher (0.89 mumol/g wet weight/min) than during reperfusion with medium containing glucose (0.41 mumol/g ww/min). Increasing amounts of tissue lactate prolonged maintenance of electrical function in glucose-free reperfusion. This correlation could not be found for free fatty acids. In conclusion, after a few minutes of ischemia, the brain is able to recover cellular ion transport and electrical activity without a supply of glucose, preferentially by combustion of lactate accumulated in brain tissue. This mechanism is only useful during a limited time period until the lactate accumulated during ischemia is combusted.