Scrapie of sheep and goats is the most common prion disease (or transmissible spongiform encephalopathy, TSE) of mammals and aggregates of abnormal, proteinase-resistant prion protein (PrP Sc) are found in all naturally occurring prion diseases. During active surveillance of British sheep for TSEs, 29 201 sheep brain stem samples were collected from abattoirs and analysed for the presence of PrP Sc. Of these samples, 54 were found to be positive by using an ELISA screening test, but 28 of these could not be confirmed initially by immunohistochemistry. These unconfirmed or atypical cases were generally found in PrP genotypes normally associated with relative resistance to clinical scrapie and further biochemical analysis revealed that they contained forms of PrP Sc with a relatively protease-sensitive amyloid core, some resembling those of Nor98 scrapie. The presence of these atypical forms of protease-resistant PrP raises concerns that some TSE disorders of PrP metabolism previously may have escaped identification in the British sheep population.