The possible transmission of bovine spongiform encephalopathy (BSE) agent to sheep contributed to select genetically sheep considered as resistant to prion diseases i.e., with PrP ARR/ARR genotype. Here, we report the infection of two PrP ARR/ARR genotype sheep using the cattle BSE agent inoculated by peripheral routes. Disease-associated prion protein (PrPd) was detected in the brain for one case (at 2191 days post-infection (dpi)) and only in the nervous enteric system for the other one (at 673 dpi). The electrophoretic pattern of PrPd from the obex region in this BSE challenged sheep was shown to be closer from that found in naturally scrapie-affected sheep with regard to the apparent molecular mass of the unglycosylated PrPd. Importantly, the absence of any clinical symptoms up to 6 years following experimental challenge suggests that silent carriers of the BSE agent may exist among ARR homozygous sheep. (c) 2006 Elsevier Inc. All rights reserved.