In conventional mice, murine strains of prions show highly specific phenotypes, as defined by several parameters including incubation period of disease, nature of clinical signs, western blot profile of abnormal prion protein (PrPSc), distribution of vacuoles and PrPSc in the brain. More surprisingly, this remains independent of where prions have had access to the brain, supporting the view that, through a determinism which remains obscure, the multiplication of the infectious agent and the PrP conversion process is favoured in brain specific areas. We sought to examine if the inoculation of natural scrapie strains to transgenic mice expressing ovine PrP would lead to similar findings. We have therefore 1) analysed the phenotype of the cloned ovine prion strain 127S after intraperitoneal or intracerebral infection of tg338 mice overexpressing the VRQ allele of sheep prion protein; 2) compared the cerebral PrPSc distribution of this strain with another cloned and phenotypically distinct one, LAN19K, after intravitreal injection. Our results show that 1) the apparent phenotype of the 127S strain is clearly influenced by the route of infection since intraperitoneally versus intracerebrally tg338 mice show different clinical signs, levels of PrPSc accumulation and distribution pattern of PrPSc and vacuoles in brain; 2) 127S and LAN19K show a similar propagation into the brain until the terminal stage of the disease, which was mainly restricted to the ocular projections. This common PrPSc distribution pattern strikingly differed from that obtained after intracerebral or intraperitoneal inoculation of these strains. Our data therefore suggest that, depending on the model, the capacity of prion strains to replicate in brain specific areas may be influenced by the route of infection.