The solution conformations of three polyhydroxymonoamide renin inhibitors which differ in the relative configuration and position of the hydroxyl groups at the P3 position were investigated by NMR spectroscopy. The NMR data are consistent with a predominant conformation in DMSO with the exception that two inhibitors exhibit conformational averaging about a torsion angle along P3. Comparisons with the renin-bound structures determined by X-ray crystallography [Tong et al., (1995) J. Mol. Biol. 250, 211] show that the unbound and renin-bound conformations are similar (with exceptions in the P3 position). This similarity suggests that gross conformational changes of the inhibitor are not a prerequisite for binding to renin. Apart from being able to tolerate different dihydroxylated structures at P3, renin can also accommodate different conformations at P3. Differences were observed at the P3 position between the inhibitors in the unbound state, between the unbound and renin-bound states, and between the renin-bound states.