To clarify the role of anoxic depolarization (AD) in ischemic brain injury, we examined the correlation between AD and ischemia-induced neuronal injury. Twenty-eight rats underwent transient forebrain ischemia with lowering of blood pressure and bilateral carotid occlusion while direct current shifts, electrocorticogram, and cortical blood now (CoBF) were epidurally recorded from the right parietal cortex. One week later the right parietal cortex was studied histopathologically. AD appeared 0.5-3.0 min after carotid occlusion in 21 of 28 animals. Circulation was reinitiated 15 min after AD onset in 11 rats (group A) and 10 min after onset in 10 rats (group B). AD did not develop during 20 min of ischemia in 7 rats (group C). All 12 rats (6 from group A and 6 from group B) in which CoBF decreased below 9.5% of control flow exhibited AD. Histopathologic examination disclosed massive neuronal necrosis in 5 of the 6 group A animals with marked now reduction but in none from group B. CoBF fell between 9.5% and 20% in 14 rats, among these, AD appeared in 9 (5 from group A and 4 from group B) but not in 5 (group C). Massive neuronal necrosis was demonstrated in 3 of 5 rats from group A. Ischemic neuronal changes were absent or minimal in only 1/5 of group A animals, a much lower fraction than in group B (4/4, p < 0.05) or in group C (5/5, p < 0.05). When CoBF remained above 20% of control flow during ischemia (2 rats) no AD or irreversible injury occurred. The present study suggests that AD is a more reliable determinant of irreversible brain injury than degree of CBF reduction, and also demonstrates that 15 min is the critical duration of AD for irreversible brain injury at brain temperatures around 37 degrees C.