To investigate whether aggravation of damage in hyperglycemic subjects is a continuous function of changes in intra- and extracellular pH during ischemia or whether there is a threshold value, preischemic plasma glucose was varied from 8.3-20.0 mM. 10 min forebrain ischemia was induced. The results showed that no animal with plasma glucose of < 13 mM developed seizures, and that all animals with glucose of > 16 mM died in status epilepticus. Half of the animals with plasma glucose in the range of 13-16 mM showed seizures and 50% of these died. In surviving animals, histological brain damage occurred in the hippocampal CA3 sector, cingulate cortex, thalamic nuclei and substantia nigra, structures normally not injured by 10 min ischemia. The data demonstrate that there is a glucose threshold of 10-13 mM, above which seizures develop and additional damage appears, and another one (> 16 mM), above which seizures are invariably fatal.