Water molecules connect 6.5 × 4.5 Å diameter rings in the X-ray crystal structure of 16-member tetrapeptide cyclo(Phe-Pro-Leu-Aha) (1) trihydrate. However, stereoisomer cyclo(D-Phe-Pro-Leu-Aha) (2) crystallized in anhydrate form. Structural differences in L- to D-amino acid exchanged cyclic peptides are analyzed.