Cortical spreading depression (SD) has not been shown in the human neocortex by direct cortical recordings. However, animal studies suggest that cortical injury, such as that occurring during neurosurgical procedures, should result in the initiation of SD. It is possible that inhibition of SD by volatile anesthetic agents may partially explain the failure to observe SD in the human neocortex during surgery. This study examines the effect of the anesthetic agents α‐chloralose, halothane, nitrous oxide and isoflurane on the initiation of cortical SD in the cat neocortex. SD was seen in 100% of cats anesthetized with α‐chloralose (n = 15), in 3 of 7 (42%) animals anesthetized with isoflurane (p < 0.05, χ² with Yates correction) and none of the animals (n = 4, 6 hemispheric preparations) anesthetized with halothane (p < 0.005, χ² with Yates correction, halothane vs α‐chloralose group). In all cases this inhibitory effect was reversible. In four animals the administration of nitrous oxide (66%) reduced the inspired concentration of isoflurane required to inhibit SD by 0.75%. This study suggests that halothane, and to a lesser extent isoflurane and nitrous oxide, protect against the initiation of cortical SD. This observation may partially explain why SD has not been demonstrated in human neocortex during surgery. Further studies are needed to determine if SD may occur under pathological conditions, such as during migraine with aura, where the cortex may be predisposed to SD.