This paper seeks to understand how a macrocyclic beta-sheet peptide inhibits the aggregation of the tau-protein-derived peptide Ac-VQIVYK-NH2 (AcPHF6). Previous studies established that macrocyclic beta-sheet peptide 1 inhibits AcPHF6 aggregation, while the sequence isomer in which the lysine and leucine residues at positions R-6 and R-7 are swapped has little effect on AcPHF6 aggregation. The current studies find that positions R-1, R-3, and R-7 are especially sensitive to mutations. Reducing hydrophobicity at these positions substantially diminishes inhibition. Although position R-5 is not sensitive to mutations that reduce hydrophobicity, it is sensitive to mutations that increase hydrophobicity. Enhanced hydrophobicity at this position substantially enhances inhibition. These studies establish that the hydrophobic surface comprising residues R-1, R-3, and R-7 is crucial to the inhibition process and that the residue R-5, which shares this surface, is also important. Collectively, these findings demonstrate that hydrophobic surfaces between beta-sheet layers are important in inhibiting amyloid aggregation.