By an extension of our simple, molecular size-based model recently developed to describe octanol-water partition coefficients, we were able to obtain an entirely structure-based model that seems well suited to describe human skin permeability data. The corresponding equations not only eliminate the physicochemical interrelatedness of the parameters of the original Potts & Guy approach that was obtained from similar considerations, but also maintain its elegant simplicity and are consistent with a basic physicochemical model of the related phenomena. As the new model is structure based and fully computerized, it allows direct estimation of skin permeability for any molecule of known structure without the need to obtain octanol-water partition coefficients or other experimental data.