Strong affinity and high selectivity are desirable characteristics of hosts in host−guest chemistry. Because starands exhibit high rigidity and sphericity, one would expect them to have interesting properties. We have investigated and predicted the complexation behavior of [16]starand with various alkali metal ions, using free energy perturbation and molecular dynamics methods. Our calculated geometries and energetics with the AMBER force field agree with previous ab initio results; energy minimization also predicts that the Li+ binds not at the center but on the outside of the cavity. Additionally, we have calculated the binding free energy differences for various alkali metal ions. The results from the gas phase simulations show that the binding free energy difference decreases as the radius increases, with only a small difference between the binding enthalpy difference and binding free energy difference. This small entropy effect in the gas phase is likely due to the structural rigidity of starand and the strong cation−ligand interactions. When the complexes lie immersed in water, the order of binding free energies reverses, i.e., the binding energy increases as the ionic radius increases. This reversal of order is thus due to the solvent effect. To investigate why water favors complexation with larger ions, we performed radial distribution function (RDF) analyses from alkali ions to water oxygens. Water coordination numbers for the free solvated ions and for those in complexes were obtained from the RDF data. The relative free energy of binding seems to be related to the solvation energy of alkali metal ions. We have also calculated the absolute binding free energies of Rb+ and Cs+ in water. Notwithstanding our expectation from the appearance of this host, these calculations predict that the alkali metals do not bind strongly to [16]starand in water. These results further demonstrate the important contribution of hydration in host−guest chemistry.