The formation of nonfibrillar oligomers has been proposed to be a common element of the aggregation pathway of amyloid peptides. Here we describe the first detailed investigation of the morphology and secondary structure of stable oligomers formed by a peptide comprising residues 106-126 of the human prion protein (PrP). These oligomers have an apparent hydrodynamic radius of approximately 30 nm and are more membrane-active than monomeric or fibrillar PrP(106-126). Circular dichroism and solid state NMR data support formation of an extended beta-strand by the hydrophobic core of PrP(106-126), while negative thioflavin-T binding implies an absence of cross-beta structure in nonfibrillar oligomers.