The aqueous chemistry of water films confined between clay mineral surfaces remains an important unknown in predictions of radioelement migration from radioactive waste repositories. This issue is particularly important in the case of long-lived anionic radioisotopes Embedded Image which interact with clay minerals primarily by anion exclusion. For example, models of ion migration in clayey media do not agree as to whether anions are completely or partially excluded from clay interlayer nanopores. In the present study, this key issue was addressed for Cl− using MD simulations for a range of nanopore widths (6 to 15 Å) overlapping the range of average pore widths that exists in engineered clay barriers. The MD simulation results were compared with the predictions of a thermodynamic model (Donnan Equilibrium model) and two pore-scale models based on the Poisson-Boltzmann equation under the assumption that interlayer water behaves as bulk liquid water. The simulations confirmed that anion exclusion from clay interlayers is greater than predicted by the pore-scale models, particularly at the smallest pore size examined. This greater anion exclusion stems from Cl− being more weakly solvated in nano-confined water than it is in bulk liquid water. Anion exclusion predictions based on the Poisson-Boltzmann equation were consistent with the MD simulation results, however, if the predictions included an ion closest approach distance to the clay mineral surface on the order of 2.0 ± 0.8 Å. These findings suggest that clay interlayers approach a state of complete anion exclusion (hence, ideal semi-permeable membrane properties) at a pore width of 4.2 ± 1.5 Å.