The active, large-scale testing of livestock nervous tissues for the presence of protease-resistant prion protein (PrPres) has led to the recognition of 2 uncommon PrPres molecular signatures, termed H-type and L-type BSE. Their experimental transmission to various transgenic and inbred mouse lines unambiguously demonstrated the infectious nature of such cases and the existence of distinct prion strains in cattle. Like the classical BSE agent, H- and L-type (or BASE) prions can propagate in heterologous species. In addition L-type prions acquire molecular and neuropathologic phenotypic traits undistinguishable from BSE or BSE-related agents upon transmission to transgenic mice expressing ovine PrP (VRQ allele) or wild-type mice. An understanding of the transmission properties of these newly recognized prions when confronted with human PrP sequence was therefore needed. Toward this end, we inoculated mice expressing human PrP Met129 with several field isolates. Unlike classical BSE agent, L-type prions appeared to propagate in these mice with no obvious transmission barrier. In contrast, we repeatedly failed to infect them with Htype prions. Ongoing investigations aim to extend the knowledge on these uncommon strains: are these agents able to colonize lymphoid tissue, a potential key factor for successful transmission by peripheral route; is there any relationship between these assumedly sporadic forms of TSE in cattle and some sporadic forms of human CJD are among the issues that need to be addressed for a careful assessment of the risk for cattle-to-human transmission of H- and L-type prions.