Alzheimer's disease (AD) is a neurodegenerative disorder pathologically characterized by extensive extracellular deposition of amyloid-beta (A beta) peptides as senile plaques, and inhibition of "amyloidogenic" amyloid precursor protein (APP) processing by gamma-secretase is an important strategy for prevention and treatment of AD. Here we show that beta-peptide foldamers designed to adopt a 12-helical conformation in solution are potent and specific inhibitors of gamma-secretase. Subtle modifications that disrupt helicity substantially reduce inhibitory potency, suggesting that helical conformation is critical for effective inhibition. These beta-peptides competed with helical peptide-type inhibitor, suggesting that they interact with the substrate binding site of gamma-secretase. The beta-peptide with inhibitory activity at nanomolar concentration should be a useful lead compound for development of gamma-secretase-specific inhibitors and molecular tools to explore substrate recognition by intramembrane proteases.