In vitro hippocampal slices from adult rats were subjected to transient hypoxia in the presence of a cell-penetrating, calpain inhibitor (Cbz-Val-Phe-H; MDL-28170). The posthypoxic recovery of synaptic potentials was greatly improved in protease inhibitor-treated slices relative to control slices. These findings support a role for calcium-activated proteolysis in the process of hypoxic pathophysiology.