Transmissible spongiform encephalopathies can be transmitted via the oral route. The understanding of this mode of contamination has become a major issue since it is responsible for the appearance of bovine spongiform encephalopathy (BSE) and is probably implicated in new variant Creutzfeldt-Jakob disease. In this study, we addressed the questions of the propagation pathway and the strain specificity of the pathogenesis of oral contamination of mice with the C506M3 scrapie strain and the 6PB1 BSE strain. PrPres was used as a marker of infectivity and was searched for sequentially in 22 organs during the whole incubation period and clinical stage. PrPres was first detectable in the Peyer's patches and mesenteric lymph nodes at 45 days post-inoculation. It became detectable 1 to 3 months later in the other tissues of the lymphoreticular system (LRS) such as the spleen and the lymph nodes not related to the digestive tract. These data indicate that after an oral route of entry, the infectious agent is propagated from the Peyer's patches to the mesenteric lymph nodes by the lymphatic route, then enters the bloodstream and is distributed to the secondary replication site, the LRS. The major difference between the two agents is that PrPres could be detected in the digestive tract (from the stomach to the colon) with the scrapie agent only. This observation may have implications for the horizontal transmission of scrapie in endemically affected sheep flocks.