An immunoperoxidase method was used to demonstrate expression of HLA-DR (a Class II major histocompatibility antigen) as an indicator of microglial activation in cases of hippocampal sclerosis derived from temporal lobectomy for intractable seizures. HLA-DR-immunoreactive microglia were increased approximately 11-fold in CA1 and 3-fold in CA3, compared to control autopsy hippocampus. The numbers of HLA-DR-immunoreactive perivascular cells were also significantly increased in hippocampal sclerosis cases (9-, 7- and 6-fold increases in CA1, CA3 and CA2, respectively). Since animal studies have found microglial activation to be an acute or subacute response to injury, the results presented here suggest that, contrary to the classical conception of human hippocampal sclerosis as an inert scar, neuronal injury continues to occur as a result of ongoing seizure activity.