Interictal spikes (IISs) represent burst firing of a small focal population of hypersynchronous, hyperexcitable cells. Whether cerebral blood flow (CBF) is adequate to meet the metabolic demands of this dramatic increase in membrane excitability is unknown. Positron emission tomography, single photon emission computed tomography, and functional magnetic resonance imaging studies have shown increases in CBF and hypometabolism, thus indicating the likelihood of adequate perfusion. We measured tissue oxygenation and CBF in a rat model of IIS using oxygen electrodes and laser-Doppler flowmetry. A ∼3-second dip in tissue oxygenation was shown, followed by more prolonged tissue hyperoxygenation, in spite of a 25% increase in CBF. Increases in the number of spikes, as well as in their amplitude and spike width further amplified these responses, and a decrease in interspike interval decreased the CBF response. Altering the anesthetic did not influence our results. Taken together, these findings indicate that frequent, high-amplitude IISs may produce significant tissue hypoxia, which has implications for patients with epilepsy and noninvasive techniques of seizure localization.