In the prion diseases, extensive reactive gliosis is often found to be out of proportion to the degree of apparent neuronal damage. To evaluate the role of astrocytic gliosis in experimental scrapie of the mouse, we inoculated mice deficient in apolipoprotein E (apoE) or the glial fibrillary acidic protein (GFAP) with mouse prions. The expression of both apoE and GFAP in astrocytes increases as part of the reactive gliosis that accompanies scrapie. Null mice deficient in either apoE or GFAP inoculated with prions exhibited incubation times indistinguishable from untargeted control mice. The level of PrPSc and its regional deposition in the brains of ill mice deficient in either protein were also similar to control mice. Our findings demonstrate that neither apoE nor GFAP participates in the pathogenesis of the disease or in the production of PrPSc.