This paper describes studies of a series of macrocyclic beta-sheet peptides 1 that inhibit the aggregation of a tau-protein-derived peptide. The macrocyclic beta-sheet peptides comprise a pentapeptide "upper" strand, two delta-linked ornithine turn units, and a "lower" strand comprising two additional residues and the beta-sheet peptidomimetic template "Hao". The tau-derived peptide Ac-VQIVYK-NH2 (AcPHF6) aggregates in solution through beta-sheet interactions to form straight and twisted filaments similar to those formed by tau protein in Alzheimer's neurofibrillary tangles. Macrocycles 1 containing the pentapeptide VQIVY in the "upper" strand delay and suppress the onset of aggregation of the AcPHF6 peptide. Inhibition is particularly pronounced in macrocycles 1a, 1d, and 1f, in which the two residues in the "lower" strand provide a pattern of hydrophobicity and hydrophilicity that matches that of the pentapeptide "upper" strand. Inhibition varies strongly with the concentration of these macrocycles, suggesting that it is cooperative. Macrocycle 1b containing the pentapeptide QIVYK shows little inhibition, suggesting the possibility of a preferred direction of growth of AcPHF6 beta-sheets. On the basis of these studies, a model is proposed in which the AcPHF6 amyloid grows as a layered pair of beta-sheets and in which growth is blocked by a pair of macrocycles that cap the growing paired hydrogen-bonding edges. This model provides a provocative and appealing target for future inhibitor design.