Analyses of trajectories generated in molecular dynamics (MD) computer simulations and pulse-field-gradient spin-echo nuclear magnetic resonance (PGSE NMR) experiments were used to investigate the molecular origin of the anomalous solubility of beta-cyclodextrin (CD) in water. The solubility of beta-CD (seven glucose units) is 1 order of magnitude lower compared with alpha- and gamma-CDs, which comprise six and eight glucose residues, respectively. The translational diffusion coefficients derived from NMR and MD are in good agreement and reveal a small but significant deviation from the molecular mass dependence. The beta-CD is seen to increase the local water structure dramatically while its internal motion displays a smaller amplitude and faster relaxation of the macrocyclic structure compared with the two other compounds. These results collectively indicate that the relatively rigid macrocyclic structure of beta-CD strongly affects the surrounding water ordering, thereby lowering the configurational entropy that results in the well-known anomaly of the beta-CD water solubility.