The clinical course, neuropathological features, and genetic findings in 3 members of a German family carrying a novel 120-bp insertion in the prion protein (PrP) gene are described. Genetic analysis of the mutated allele revealed a sequence of five extra octapeptide repeats, distinct from those of the two previously reported families with an insertion of this size. There was distinctive variation in the clinical course and the onset and duration of the illness in the documented subjects. Neuropathological evaluation showed neuronal loss and gliosis in the neocortex of the 3 examined cases; spongiform degeneration was found in 2 of them. PrP immunoreactivity of unusual morphology and distinct distribution was present in the cerebellum and neocortex (“blurred staining”) of 2 examined cases. One subject showed features usually found in sporadic Creutzfeldt-Jakob disease with a punctate type of PrP deposition in the cerebellum. In addition, there were some plaque-like PrP aggregates morphologically similar to the other 2 cases in the molecular layer of the cerebellum, and unusual PrP immunoreactivity (“fleecy staining”) was found in the neocortex. The clinicopathological heterogeneity in the documented family is in accordance with the phenotypic variability associated with previously reported insertions.