Chronic wasting disease (CWD), a progressive neurological disorder of captive mule deer and Rocky Mountain elk, is characterized neuropathologically by widespread spongiform change of the neuropil, intracytoplasmic vacuolation of the neuronal perikarya and astrocytic hypertrophy and hyperplasia. Histochemically demonstrable amyloid plaques and amyloid plaques reactive to antibodies prepared against scrapie amyloid in captive mule deer, mule deer hybrids and Rocky Mountain elk naturally affected with CWD are presented. Amyloid plaques in CWD-affected mule deer were congophilic, birefringent and periodic acid-Schiff (PAS) positive. In mule deer hybrids, only occasional PAS-positive plaques were observed. No histochemically demonstrable plaques were observed in CWD-affected Rocky Mountain elk. Antibody raised against scrapie amyloid showed robust immunoreactivity with amyloid plaques in CWD-affected captive mule deer and were found in the cerebral grey and white matter in clusters or in isolation, in deep subcortical nuclei, in all layers of the cerebellum, in areas of extensive vacuolation and in subpial and perivascular regions. In hybrid deer, plaques were rarely observed in cerebellum and subpia. A notable finding in brain sections of CWD-affected hybrid deer and Rocky Mountain elk was a circumscribed collection of scrapie amyloid-immunopositive nuclei with non-congophilic, non-birefringent amyloid deposits located at its center. In elk, plaques were not observed in cerebellum, subpia and subependyma. Furthermore, amyloid plaques in CWD-affected captive mule deer were alcianophilic at 0.3 M magnesium chloride indicating the presence of weakly to moderately sulfated glycosaminoglycans. Similar scrapie amyloid-immunoreactive plaques are also present in Creutzfeldt-Jakob disease, Gerstmann- Straussler syndrome and kuru in humans. The data presented here corroborate that CWD belongs to the subacute spongiform virus encephalopathies (transmissible cerebral amyloidoses).