A conformational change seems to represent the major difference between the scrapie prion protein (PrP Sc ) and its normal cellular isoform (PrP C ). We recently proposed a set of four helix bundle models for the three-dimensional structure of PrP C that are consistent with a variety of spectroscopic and genetic data. We report a plausible model for the three-dimensional structure of a biologically important fragment of PrP Sc . The model of residues 108–218 was constructed by an approach that combines computational techniques and experimental data. The proposed structures of this fragment of PrP Sc display a four-stranded β-sheet covered on one face by two α-helices. Residues implicated in the prion species barrier are found to cluster on the solvent-accessible surface of the β-sheet of one of the models. This interface could provide a structural template that would assist the conversion of PrP C to PrP Sc and hence direct prion propagation. Molecular models of the PrP isoforms should prove very useful in developing structural hypotheses about the process by which PrP C is transformed into PrP Sc , the mechanisms by which PrP gene mutations give rise to the inherited human prion diseases, and the species barrier that seems to protect humans from animal prions. It seems likely that PrP C represents a kinetically trapped intermediate in PrP folding.