The NMR structure of the recombinant elk prion protein (ePrP), which represents the cellular isoform (ePrP^C) in the healthy organism, is described here. As anticipated from the highly conserved amino acid sequence, ePrP^C has the same global fold as other mammalian prion proteins (PrPs), with a flexibly disordered “tail” of residues 23–124 and a globular domain 125–226 with three α-helices and a short antiparallel β-sheet. However, ePrP^C shows a striking local structure variation when compared with most other mammalian PrPs, in particular human, bovine, and mouse PrP^C. A loop of residues 166–175, which links the β-sheet with the α2-helix and is part of a hypothetical “protein X” epitope, is outstandingly well defined, whereas this loop is disordered in the other species. Based on NMR structure determinations of two mouse PrP variants, mPrP[N174T] and mPrP[S170N,N174T], this study shows that the structured loop in ePrP^C relates to these two local amino acid exchanges, so that mPrP[S170N,N174T] exactly mimics ePrP^C. These results are evaluated in the context of recent reports on chronic wasting disease (CWD) in captive and free-ranging deer and elk in the U.S. and Canada, and an animal model is proposed for support of future research on CWD.