Little is known about effect of conformation on passive membrane diffusion rates in small molecules. Evidence suggests that intramolecular hydrogen bonding may play a role by reducing the energetic cost of desolvating hydrogen bond donors, especially amide N-H groups. We set out to test this hypothesis by investigating the passive membrane diffusion characteristics of series of cyclic peptide diastereomers based on the sequence cyclo[Leu Leu Leu Leu Pro Tyr]. We identified two cyclic hexapeptide diastereomers based on this sequence whose membrane diffusion rates differed by nearly two log units. Results of solution NMR studies and hydrogen/deuterium exchange experiments showed that membrane diffusion rates correlated with the degree of intramolecular hydrogen bonding and H/D exchange rates. The most permeable diastereomer, cyclo[DLeu-DLeu-Leu-DLeu-Pro-Tyr] (1), exhibited a passive membrane diffusion rate comparable to the orally available drug cyclosporine A.