Prion diseases are associated with the conformational conversion of the cellular prion protein (PrP C) into the pathological scrapie isoform (PrP Sc) in the brain. Both the in vivo and in vitro conversion of PrP C into PrP Sc is significantly inhibited by differences in amino acid sequence between the two molecules. Using protein misfolding cyclic amplification (PMCA), we now report that the recombinant full-length human PrP (rHuPrP23-231) (that is unglycosylated and lacks the glycophosphatidylinositol anchor) is a strong inhibitor of human prion propagation. Furthermore, rHuPrP23-231 also inhibits mouse prion propagation in a scrapie-infected mouse cell line. Notably, it binds to PrP Sc, but not PrP C, suggesting that the inhibitory effect of recombinant PrP results from blocking the interaction of brain PrP C with PrP Sc. Our findings suggest a new avenue for treating prion diseases, in which a patient's own unglycosylated and anchorless PrP is used to inhibit PrP Sc propagation without inducing immune response side effects.