A case was reported of variant Gerstmann-Sträussler-Scheinker disease (GSS) carrying codon 105 mutation (Pro to Leu) with codon 129 polymorphism (Met/Val) of the prion protein (PrP) gene. The male patient had developed clumsiness of the right hand at age 42, and subsequently exhibited slowly progressive spastic paraparesis, ataxia, dysarthria, memory disturbance and apraxia. Myoclonus or periodic synchronous discharge was not observed. He died at age 53. The cerebral cortex and white matter showed atrophy, which was prominent in the frontal regions. There were numerous amyloid plaques throughout the cerebral cortex, which were reactive with the antibody to PrP, but not to beta/A 4 peptide. PrP immunostaining also revealed many amorphous deposits in the deep cortical layers, where neuronal loss and glial proliferation was evident. The cerebellum was almost intact, except a few amyloid plaques in the white matter. This variant GSS with codon 105 mutation has been found in four pedigrees, only in Japan up to the present, and the clinicopathological phenotype is summarized as follows: (1) onset at age 38-48, with a duration of 7-11 years, (2) prominent spastic paraparesis, associated with dementia and ataxia, (3) numerous amyloid plaques in the cerebral cortex, (4) amorphous PrP deposits with neuronal loss in the deep cortical layers, and (5) minor change of cerebellum.