The binding affinities between a united-atom methane and various model hydrophobic enclosures were studied through high accuracy free energy perturbation methods (FEP). We investigated the non-additivity of the hydrophobic interaction in these systems, measured by the deviation of its binding affinity from that predicted by the pairwise additivity approximation. While only small non-additivity effects were previously reported in the interactions in methane trimers, we found large cooperative effects (as large as −1.14 kcal mol⁻¹ or approximately a 25% increase in the binding affinity) and anti-cooperative effects (as large as 0.45 kcal mol⁻¹) for these model enclosed systems. Decomposition of the total potential of mean force (PMF) into increasing orders of multi-body interactions indicates that the contributions of the higher order multi-body interactions can be either positive or negative in different systems, and increasing the order of multi-body interactions considered did not necessarily improve the accuracy. A general correlation between the sign of the non-additivity effect and the curvature of the solute molecular surface was observed. We found that implicit solvent models based on the molecular surface area (MSA) performed much better, not only in predicting binding affinities, but also in predicting the non-additivity effects, compared with models based on the solvent accessible surface area (SASA), suggesting that MSA is a better descriptor of the curvature of the solutes. We also show how the non-additivity contribution changes as the hydrophobicity of the plate is decreased from the dewetting regime to the wetting regime.