Objective: To describe a novel molecular and pathological phenotype of Creutzfeldt-Jakob disease. Patient: A 69-year-old woman with behavioral and personality changes followed by rapidly evolving dementia. Results: Postmortem examination of the brain showed intracellular prion protein deposition and axonal swellings filled with amyloid fibrils. Biochemical analysis of the pathological prion protein disclosed a previously unrecognized PrP(Sc) tertiary structure lacking diglycosylated species. Genetic analysis revealed a wild-type prion protein gene. The prion agent responsible for this atypical phenotype was successfully passaged to bank voles. Conclusion: To our knowledge, our results define a new human prion disorder characterized by intracellular accumulation of a novel type of pathological prion protein