Rasmussen's encephalitis is a progressive epileptic disorder characterized by unihemispheric lymphocytic infiltrates, microglial nodules, and neuronal loss leading to the destruction of the affected hemisphere. In this study, immunohistochemical evaluation of specimens from 11 patients revealed lymphocytic infiltrates that consisted mainly of CD3(+)CD8(+) T cells. Of these cells, 7.0% lay in direct apposition to MHC class I(+) neurons. Confocal laser microscopy revealed that these lymphocytes contained granzyme B in a polar orientation toward these perikarya. Single neurons underwent apoptosis. These findings indicate that a T-cell-mediated cytotoxic reaction induces neuronal death in Rasmussen's encephalitis. This study directly shows, for what we believe is the first time, that a cytotoxic T-cell mechanism contributes to loss of neurons in human brain disease.