We compared interstitial ion concentrations in rat brain cortex during two conditions where pronounced changes are observed: spreading depression and ischemia. Initially, during the two phenomena, an increase of [K + ] e from 3 to approximately 10 mM were observed, but only small changes of the other ion concentrations. Hereafter, [K + ] e exhibited a rapid increase (2–3 s) to 55 mM, whereas [Na + ] e rapidly decreased to 60 mM, [Cl ‐ ] e to 75 mM, and [Ca ++ ] e to 0.08 mM. The changes were accompanied by a rapid negative shift in the local electrical potential. However, there were differences in the ionic events during the two phenomena. In spreading depression, the initial [K + ] e increase took place in 5–10 s, but in ischemia it lasted 1–2 min. The ionic perturbations were spontaneously reverted in SD, but in ischemia they proceeded further and reached after 5 min (mM): [K + ] e 75, [Na + ] e 50, [Cl ‐ ] e 72, and [Ca ++ ] e 0.06. The similar chain of ionic events during spreading depression and ischemia suggests a common mechanism for the ionic changes, probably involving changes of ionic permeability of brain cells.