Because ARR/ARR genotype sheep were considered to be totally resistant to TSE oralcontamination, they are massively selected in order to protect human food chain from smallruminant BSE risk.A controversial natural scrapie ARR/ARR case was reported in 1994, but genotype of that animalwas never confirmed. Recent identification of (i) atypical abnormal PrP accumulation inasymptomatic animals and (ii) successful transmission of BSE after intracerebral challenge bothraised new concerns about the resistance of ARR/ARR genotype sheep towards natural Priondiseases.However since neither PrPSc nor infectivity was reported in peripheral tissue from the orally orintracerebrally BSE challenged ARR/ARR animals (Bellworthy et al., 2005; Jeffrey et al., 2001).The ‘breeding for resistance’ policy aiming at protecting human food chain was not affected.In a first study, TSE free ARR/ARR and ARQ/ARQ lambs were orally challenged with 5g ofBSE infected sheep brain material. Strikingly, in one challenged ARR/ARR animal, PrPSc wasobserved in spleen at 10 months post challenge. ELISA and WB allowed estimating the totalPrPSc amount in ARR/ARR spleen to be 5 to 10 fold lower than in ARQ/ARQ.In a second study TSE free ARQ/ARQ and ARR/ARR sheep were IC challenged with BSE. Insymptomatic animals from both genotypes, PrPSc was detected in samples from a large panel ofskeletal muscle.Finally the retrospective study of a large scrapie tissue bank allowed us to identify a classicalscrapie case in an ARR/ARR field flock animal.Taken together all those data suggest that ARR/ARR sheep could be lowly susceptible to naturalTSE. It also raises new questions about (i) the pathogenesis and contagiousness of Prion diseasein animals bearing that genotype and (ii) the potential consequence for human food chain.