Halothane is a strong inhibitor of potassium evoked spreading depression (SD) in cats. In the current study, we investigate halothane effects on induction of perifocal SD-like depolarizations, CBF, and infarct evolution in focal ischemia. Calomel and platinum electrodes measured cortical direct current potential and CBF in ectosylvian, suprasylvian, and marginal gyri. Left middle cerebral artery occlusion (MCAO) induced permanent focal ischemia for 16 hours in artificially ventilated cats (30% oxygen, 70% nitrous oxide) under halothane (0.75%, n = 8) or alpha-chloralose anesthesia (60 mg/kg intravenously, n = 7). Under alpha-chloralose, MCAO induced severe ischemia in ectosylvian and suprasylvian gyri(mean CBF < 10 mL/100 g/min), and direct current potentials turned immediately into terminal depolarization. In marginal gyri, CBF reduction was mild (more than 20 mL/100 g/min), and in six of seven animals, frequent SD-like depolarizations turned into terminal depolarization at a later stage of the experiments. Under halothane, MCAO induced severe ischemia (less than 10 mL/100 g/min) and immediate terminal depolarization only in ectosylvian gyrus. In suprasylvian gyrus, residual CBF remained significantly higher (more than 10 mL/100 g/min) than under alpha-chloralose, whereas in marginal gyri, CBF did not differ between groups. Compared with chloralose, the number of transient depolarizations was significantly reduced in marginal gyrus, and in suprasylvian gyrus transient but significantly longer depolarizations than in marginal gyrus were recorded. Except for one animal, transient depolarizations did not turn into terminal depolarization under halothane, and infarct volume reduction was particularly seen in suprasylvian gyrus. We conclude that halothane, the most commonly used anesthetic in studies of experimental brain ischemia, has protective properties, which may depend on both cerebrovascular and electrophysiologic influences.