Background: In Great Britain, sheep scrapie cases have been detected through active and passive surveillance programmes which do not conform to the characteristics usually associated with classical scrapie. These cases, designated as ‘atypical scrapie’, demonstrate a weak positive PrPres reaction in Bio-Rad ELISA and in histopathology produce a weak immunohistochemistry signal and demonstrate a different PrPSc distribution pattern compared to classical scrapie. Other features, such as an absence of vacuolation at the obex and a characteristic PrPres Western blotting profile are also apparent. Aim: The aim of this Defra-funded study was to determine the transmissibility of atypical scrapie cases from Britain to transgenic PrP and conventional mice, and to examine the biochemical and histopathological characteristics of the transmitted agent(s). Methods: Atypical scrapie isolates were selected from sheep carrying a range of PrP genotypes and inoculated into tg338, C57BL/6 and VM mice. Inoculated mice were clinically monitored and at termination brain samples were examined by Western blotting, lesion profiling and immunohistochemistry. Results: Eighteen atypical scrapie isolates derived from sheep of different genotypes transmitted successfully to tg338 mice at VLA and INRA. Incubation periods, lesion profiles, PrPSc distribution and Western blot profiles of the examined cases were similar, suggesting the isolation of a single strain. Furthermore, the biochemical and histopathological characteristics produced were indistinguishable from those of Nor 98 in the same transgenic mouse line. Bioassay in wild-type mice is ongoing with no TSE positive mice identified up to 431 days post-inoculation. Conclusion: Our findings suggest that the atypical scrapie cases from GB represent infection resulting from a single strain of TSE agent that is indistinguishable from Nor98.