BACKGROUND AND PURPOSE: Spreading depolarizations, characterized by large propagating, slow potential changes, have been demonstrated with electrocorticography in patients with cerebral hemorrhage and ischemic stroke. Whereas spreading depolarizations are harmless under normal conditions in animals, they cause or augment damage in the ischemic brain. A fraction of spreading depolarizations is abolished by N-methyl-d-aspartate receptor antagonists. Summary of Case- In 2 patients with severe acute brain injury (traumatic and spontaneous intracranial hemorrhage), spreading depolarizations were inhibited by the noncompetitive N-methyl-d-aspartate receptor antagonist ketamine. This restored electrocorticographic activity. CONCLUSIONS: These anecdotal electrocorticographic findings suggest that ketamine has an inhibitory effect on spreading depolarizations in humans. This is of potential interest for future neuroprotective trials.