Congophilic kuru plaques, one of the pathological hallmarks in kuru and Gerstmann-Sträussler syndrome, are sometimes present in patients with Creutzfeldt-Jakob disease (CJD). The congophilic kuru plaques are composed partly of a host-encoded prion protein, and a missense variant prion protein with the codon 102 proline-to-leucine change (Leu102) is commonly present in patients with Gerstmann-Sträussler syndrome. To investigate the relationship between this syndrome and CJD with congophilic kuru plaques, we made a sequence analysis of the prion protein gene from patients with CJD, with or without congophilic kuru plaques. We found no alterations other than the Leu102 change, common to Gerstmann-Sträussler syndrome, in one of the prion protein alleles of the patient with congophilic kuru plaques. In the prion protein genotype analysis of other patients with CJD, the Leu102 allele was revealed to be carried heterozygously by 6 of 7 patients who had CJD with congophilic kuru plaques, yet no patient with CJD without congophilic kuru plaques had this allele. Interestingly, the Leu102 allele was also carried by some unaffected relatives of 3 patients with CJD with congophilic kuru plaques but with no apparent familial occurrence of a similar neurological disorder. Our findings show that CJD with congophilic kuru plaques should be categorized as belonging to Gerstmann-Sträussler syndrome, not CJD, and also suggest that the variant prion protein with Leu102 is closely related to the amyloidogenesis seen in subjects with congophilic kuru plaques.