We report here on the exuberant glial reaction in the optic nerves affected by prion diseases. Optic nerves from CJD- and GSS-, and scrapie-infected mice and hamsters showed severe pathology. These lesions were qualitatively indistinguishable from each other but were more intense in the Fujisaki model than in the hamsters inoculated with Echigo-1. Exuberant cellular reaction comprised of macrophages containing numerous mitochondria, abundant rough endoplasmic reticulum, and secondary lysosomes filled with digested myelin debris, electron-dense material and occasionally, entire myelin-bound vacuoles were readily observed in both models. Macrophages actively digesting myelin fragments and containing lyre-like bodies and paracrystalline inclusions were frequently noted. Some macrophages extended long filopodia to form labyrinth-like structures, and within a few macrophages, concentric arrays of cisterns and channels sequestrated part of the cytoplasm. An analogous network of narrow cisterns was seen to surround whole segments of the myelinated fibers.