Helix bundles are among the most widely studied tertiary and quaternary structural motifs in proteins. Here we present the crystal structure of an alpha/beta-peptide foldamer that adopts a tetrameric helix-bundle quaternary structure with a hydrophobic core composed solely of beta-amino acids. The structure displays features that are unprecedented among all known helix bundles composed of either a-peptides or peptidic foldamers. The tetramer is characterized by an asymmetry of interaction between neighboring hetices, and the side-chain packing within the hydrophobic core differs fundamentally from the knobs-into-holes arrangement typical of most helix bundles.