Bovine spongiform encephalopathy (BSE) was first identified in Great Britain (GB) in 1986 and was subsequently detected in many other countries, world-wide. A decade after the start of the bovine epidemic, the first cases of new variant Creutzfeldt-Jakob disease (vCJD) in humans were linked to probable ingestion of BSE infected tissue, highlighting a new zoonotic disease. An abnormal protease-resistant protein (PrPres) in a diseased subject, derived from a post-translational change of a normal host cellular membrane protein (PrPc), is a reliable disease marker for the whole group of neurodegenerative transmissible spongiform encepalopathies (TSEs). Immunology-based techniques, such as Western immunoblotting, have previously indicated that BSE cases all give a uniform molecular profile for PrPres. Periodic lesion profiling of the spongiform change throughout different brain regions of infected mice and cattle has also indicated a single agent for BSE. However, in 2001 rapid testing for PrPres was introduced for the active surveillance of ruminants within Europe, and approximately 40 BSE cases have now been recognized that differ in their molecular profiles from those typically found. These unusual BSE cases have been detected in several European countries, and in Japan and the USA. At present, the cases appear as two distinct types based on the molecular mass (Mm) of the unglycosylated PrPres protein band relative to that of classical BSE. One type is of a higher Mm (H-type) and the other shows a lower Mm (L-type). Transmission studies in mice have shown that both H-type and L-type BSE have biological characteristics that are different from those of the classical BSE agent. This study describes the prion protein (PRNP) genotype and molecular profiles of the first two cases of H-type BSE detected in GB in comparison with those obtained for classical BSE, scrapie in sheep from GB and a control H-type BSE case from France.