Data from the records of patients who underwent 2223 carotid endarterectomies at the Mayo Clinic between January 1, 1972, and December 31, 1985, were abstracted to compare the effects of isoflurane, enflurane, and halothane on the critical cerebral blood flow (CBF) (i.e., the CBF below which the majority of patients develop EEG ischemic changes within 3 min of carotid occlusion), the incidence of EEG ischemic changes, and the neurologic outcome. In a total of 2196 of these procedures, the patient received one of the three volatile anesthetics and, in 2010 of these, both the EEG and the CBF were monitored. Chronologically, halothane was the primary agent from 1972–1974; enflurane progressively replaced halothane during 1975–1981; and isoflurane was used almost exclusively since 1982. This analysis confirmed a previous study that the critical CBF during isoflurane anesthesia (703 procedures) was approximately 10 ml ± 100 g−1 • min−1, as contrasted to that of approximately 20 ml ± 100 g−1 • min−1 during halothane anesthesia (467 procedures). This analysis also established that the critical CBF during enflurane anesthesia (840 procedures) was approximately 15 ml ± 100 g−1 • min−1. The incidence of EEG ischemic changes was significantly less (P < 0.001) during isoflurane anesthesia (18%) than during either enflurane (26%) or halothane (25%) anesthesia. This difference occurred despite the fact that the preoperative risk status was greater in the patients given isoflurane. There was no difference in neurologic outcome between the three anesthetics, and none was expected, since all patients with EEG changes were immediately shunted, if possible. The authors conclude that relative to halothane and enflurane, isoflurane does offer a degree of cerebral protection for transient incomplete regional cerebral ischemia during carotid endarterectomy.