BACKGROUND: The risk of transmissible spongiform encephalopathy (TSE) transmission by blood transfusion is dependent on the blood concentrations of the pathologic isoform of prion protein (PrPsc) but may also be influenced by blood concentrations of cellular PrP (PrPc). These concentrations are controlled by the blood clearance of PrP, which has never been evaluated. STUDY DESIGN AND METHODS: The blood (actually plasma) clearance of ovine purified prokaryote recombinant PrP (rPrP) was measured in genotyped and in nephrectomized sheep. The exposure to proteinase Kresistant fragments of PrP (PrPres) after intravenous (IV) administration of scrapie-associated fibrils (SAFs) was also investigated in a sheep. RESULTS: The ARR variant of rPrP was eliminated more rapidly than its VRQ counterpart. The PrPc plasma concentrations in homozygous highly susceptible VRQ sheep were greater than in homozygous ARR-resistant sheep, suggesting that clearance of the ARR variant of PrPc was higher than that of the VRQ variant. The plasma clearance of rPrP was decreased by 52 percent after a bilateral nephrectomy indicating the significant contribution of the kidneys in eliminating rPrP. PrPres was shown to be slowly eliminated after IV administration of scrapie-associated fibrils. CONCLUSION: PrP host genotype and physiopathologic factors could influence the risk of TSE transmission by modulating blood PrP clearance. This risk was increased by the sustained exposure to PrPres after IV administration. It should be noted that although the materials that have been administered (rPrP and SAFs) were not the actual species of interest, they can be of value as probes for investigating PrP clearance mechanisms.