We report the pathological and immunohistochemical changes in the first-order neurons in the trigeminal ganglia in Creutzfeldt-Jakob disease (CJD). Degenerative changes consisted of cytoplasmic vacuolation and fenestration, abundant satellite cells, neurofilament accumulation in neurons, and axonal dystrophy with spheroid formation and torpedolike structures arising from the neuronal cytoplasm. Dystrophic axons, axonal spheroids, and some ganglion cells were labeled with monoclonal antibodies to a phosphorylated epitope of neurofilaments (200 kDa). Polyclonal antibodies to purified scrapie-associated fibril/prion protein (molecular weight 27-30 kDa) extracted from scrapie-infected hamster brains, as well as polyclonal and monoclonal antibodies to a synthetic 15-amino acid polypeptide of the 27- to 30-kDa protein, demonstrated variable immunoreactivity with degenerating neurons in the CJD cases, but not in the controls. Furthermore, some of the satellite cells and dystrophic axons were stained by the antibodies to the synthetic peptide. These data indicate that the first-order neurons of the trigeminal ganglia may form a route by which the CJD agent may travel from the brain to the periphery or vice versa. As in other chronic neurodegenerative diseases, disturbances of neuroaxonal transport seem to occur in CJD.