Marked lateral ventricular enlargement associated with atrophic cerebral cortex and periventricular encephalitis is described in a 2-month-old fox affected by disorientation, generalized ataxia, difficulty in walking, circling, and blindness. Clinical conditions progressed to stupor and spontaneous death within a few days. At necropsy, severe inflammatory and necrotizing lesions were observed in periventricular sites associated with diverticula and cleft formation in perithalamic areas and rhinencephalic cortex. Immunolabeling for Toxoplasma gondii, Neospora caninum, Encephalitozoon cuniculi, canine distemper virus, and rabies virus was negative. Given the presence of periventricular and choroidal neutrophilic/mononuclear cell infiltration, it is thought that a bacterial infection may have been the cause of the inflammatory lesions, with internal hydrocephalus secondary to the severe periventricular lesions. A similar condition has been previously reported in the pathogenesis of spontaneously occurring acquired canine hydrocephalus, but no viral or bacterial causes have been investigated to date.