The nature of the glial and inflammatory cell responses to infection in scrapie–affected brains was studied in terminally–affected mice of Ave scrapie models. There were marked astrocytic and microglial responses. Microglia showed increased staining of the surface antigens F4/80, leucocyte–common antigen, type 3 complement receptor, and elevated endocytotic and lysosomal activity. In all models, the astrocytic and microglial responses were largely restricted to anatomical regions of the brain showing vacuolation and/or plaque formation and pathological accumulations of PrP. Expression of MHC Class II was patchy and present on microglia in the neuropil of areas with the most intense microglial activation and on occasional perivascular macrophages. This microglial response may represent a modified form of inflammatory response.