We find that host-guest binding affinities are grossly overestimated by ABFE calculations with the baseline OBC2 model, and that our HG-optimized GB cavity radii dramatically improve the accuracy, with excellent transferability to a test set comprising 90 additional host-guest systems. Importantly, the optimized parameters also transfer well to benchmark dataset of 59 protein-ligand binding free energies, demonstrating the utility of using host-guest systems as a model for binding and data for force field development. However, optimizing the GB radii to ∆G b resulted in a marked deterioration of the ability of the OBC2 model to reproduce ∆G solv . This results from the fact that the optimization against host-guest binding data drove a marked reduction of selected GB cavity radii, as needed to weaken the excessively attractive host-guest electrostatic interactions, particularly for the cucurbit[n]uril cases. However, the artificially small radii lead to excessively favorable HFEs.