PrP(C), a glycosylphosphatidylinositol-linked glycoprotein, plays a central role in the pathogenesis of transmissible spongiform encephalopathies (TSEs), undergoing a conformational alteration to the disease-associated isoform, commonly designated PrP(Sc). PrP(C) is expressed in many tissues other than the nervous system, although its precise function(s) remains unclear. It has previously been demonstrated that TSEs can be transmitted by blood transfusion in sheep. The aim of this work was to identify which components of blood carried the infection. As an initial step, the distribution of PrP(C) on cellular components of sheep blood was examined to identify potential targets for infection. Cell-surface expression of PrP(C) was found only on peripheral blood mononuclear cells (PBMCs); however, platelets also contained significant amounts of intracellular PrP(C). The level of PrP(C) expressed on the cell surface of PBMCs was influenced by PrP genotype, with the highest levels found in scrapie-susceptible VRQ/VRQ sheep and the lowest levels in scrapie-resistant ARR/ARR sheep. In susceptible sheep, PrP(C) was expressed at varying levels on all major subsets of PBMCs, with the highest levels on the CD21(+) subset of B cells, and PrP expression was upregulated dramatically on CD21(+) B cells in some scrapie-infected sheep.