The structural transition of the prion protein from alpha-helical- to beta-sheet-rich underlies its conversion into infectious and disease-associated isoforms. Here we describe the crystal structure of a fragment from human prion protein consisting of the disulfide-bond-linked portions of helices 2 and 3. Instead of forming a pair-of-sheets steric zipper structure characteristic of amyloid fibers, this fragment crystallized into a beta-sheet-rich assembly of hexameric oligomers. This study reveals a never before observed structural motif for ordered protein aggregates and suggests a possible mechanism for self-propagation of misfolded conformations by such non-amyloid oligomers.