In the aftermath of prolonged continuous seizure activity (status epilepticus, SE), neuronal cell death occurs in the brain regions through which the seizure propagates. Recent studies have implicated apoptotic processes in this seizure-related injury. Because activation of caspase-3-like cysteine proteases plays a crucial role in mammalian neuronal apoptosis, we explored the possibility that activation of caspase-3 is involved in the neuronal apoptotic cell death that occurs in rat brain following SE induced by systemic kainic acid. Caspase-3 activity was determined immunocytochemically using CM1 antibodies specific for catalytically active subunit (p17) of the enzyme. We found an induction of caspase-3 activity in rhinal cortex and amygdala at 24 h after SE. To determine whether activation of caspase-3-like proteases is a necessary component of the injury process, we delivered a caspase-3 inhibitor, z-DEVD-fmk, into the lateral ventricle prior to, and following SE. z-DEVD-fmk treatment substantially attenuated apoptotic cell death after SE, both in hippocampus and rhinal cortex, as evaluated by analysis of internucleosomal DNA fragmentation and neuronal nuclear morphology. Our findings implicate caspase-3 cysteine protease in the neurodegenerative response to SE and suggest that this degeneration can be attenuated by inhibition of caspase-3-like enzyme activity.