The application of an ensemble-averaging (EA) protocol to highlight conformational variability and to determine the interconverting conformations in NMR structure of cyclopeptides is described. Most of the NMR-based conformational studies of cyclopeptides reported in the Literature rely on protocols that basically assume the existence of a single structure. This is sometimes referred as the one NOE(or ROE)/one distance hypothesis. In contrast, the EA protocol used in this work relies on a model that explicitly takes into account the averaging in NMR data and tests the significancy of the results which is very often disregarded in structure determination by NMR. This EA method was applied to the conformational analysis of the peptide cyclo(Gly-Pro-Phe-Gly-Pro-Nle) in DMSO by NMR. Qualitative analysis of the ROEs observed for this peptide indicates that it adopts the well-known double reverse turn structure. However, certain interproton distances derived from a set of ROESY experiments, as well as some coupling constants, are not compatible with the existence of a unique conformation but reflect the presence of several conformers in fast exchange on the NMR time scale. Therefore, structures consistent as ensemble with the NMR-derived restraints were determined using a restrained molecular-dynamics-based ensemble-averaging protocol which explicitly takes multiconformers into account and treats the restraints as ensemble-averaged quantities. The NMR-derived data used as input restraints in this EA protocol include the distance restraints (DR), the homonuclear coupling constants (J), and a large set of unambiguous antidistance restraints (ADR) that are : generally disregarded in conformational analysis of cyclopeptides. The number of interconverting conformers was determined from the significance of the fit of the DR and ADR using the complete cross-validation method. The results shows that pairs of conformers give a satisfactory and significant fit of all NMR data. The conformational analysis of the interconverting partners reveals that the hexapeptide cyclo(Gly-Pro-Phe-Gly-Pro-Me) exists in solution either as a beta VIII-beta III/i gamma-beta I or a beta II-beta II/beta I-beta I equilibrium.