A case of familial Creutzfeldt-Jakob disease associated with a 144 base pair insertion in the-open reading frame of the prion protein gene is described. Sequencing of the mutated allele showed an arrangement of-six octapeptide repeats, distinct from that of a recently described British family with an insertion of similar size. Thirteen years previously the brother of the proband had died from "Huntington's disease", but re-examination of his neuropathology revealed spongiform encephalopathy and antiprion protein immunocytochemistry gave a positive result. The independent evolution of at least two distinct pathological 144 base pair insertions in Britain is proposed. The importance of maintaming a high index of suspicion of inherited Creutzfeldt-Jakob disease in cases of familial neurodegenerative disease is stressed. (J Neurol Neurosurg Psychiatry 1995;58:65-69)