Minute amounts of tetanus toxin injected into the hippocampus of rats results in an epileptiform syndrome. When the toxin injection is made unilaterally or bilaterally into the ventral hippocampus, about one-third of animals with seizures show bilateral neuronal loss in dorsal CA1 of the hippocampus after 1 week. In animals with seizures, microglia in hippocampus are found to be activated. The present work shows that during the acute phase, microglia in the substantia nigra become activated and express MHC class II antigens in the majority of animals with seizures. After the animals have recovered from the acute phase at 8 weeks, the MHC class II expression has largely disappeared from the substantia nigra but MHC class II-expressing microglia are found in the dorsal hippocampus of those rats with loss of cells from CA1. These results show that microglia are responsive to abnormal electrical activity in the central nervous system in the absence of degenerative changes. Further studies are required to determine how microglia may contribute to the neuropathology of epilepsy.