The membrane phospholipid affinity data, logkwIAM, for 14 basic drugs spanning a wide lipophilicity range were measured by HPLC on two different phospholipid stationary phases, i.e. IAM.PC.MG and IAM.PC.DD2. These data related weakly with logPN values, the n-octanol/water partition coefficients of the neutral forms; poorer relationships were found with logD7.0 values, the n-octanol/water partition coefficients of the mixtures of neutral and ionized forms at pH 7.0. The lack of collinearity confirms that, differently from partition in n-octanol/water, partition in phospholipids encodes not only lipophilic/hydrophobic intermolecular recognition forces but also ionic bonds, due to electrostatic interactions between electrically charged species and phospholipids, according to the “pH-piston hypothesis”. This component of interaction was parameterized by ΔlogkwIAM values; they are the differences between the logkwIAM values experimentally measured and the values expected for neutral isolipophilic compounds. ΔlogkwIAM values of the various analytes changed almost linearly from positive to negative values at increasing lipophilicity. This behavior is consistent with an interaction mechanism with membrane phospholipids including two intermolecular interaction forces: (i) lipophilic/hydrophobic interactions, which decrease on ionization proportionally to the lipophilicity of the neutral forms, and (ii) electrostatic interactions, which increase on ionization and are quite constant for all the analytes at a given ionization degree. Since BBB passage of the considered compounds is supposed to be based on passive mechanisms, we investigated the possible relationships between log BB values, i.e. the logarithms of the ratio between brain and blood concentrations, and three physico-chemical parameters, i.e. (i) logPN (lipophilic interaction of the neutral form), (ii) logkwIAM (global interaction with phospholipids), and (iii) ΔlogkwIAM (electrostatic component of interaction with phospholipids). The results suggest that the electrostatic interactions encoded in logkwIAM values might act as trapping forces in a phospholipid barrier. Actually, we observed an inverse linear dependence of log BB on ΔlogkwIAM values, but only for the compounds showing positive ΔlogkwIAM values. We conclude that the driving force for BBB passage is the lipophilicity of the neutral forms, logPN, and not the lipophilicity actually displayed at the experimental pH, logD7.0. Indeed, the latter does not adequately take into account the role played by protonation in the analyte/membrane interactions because protonation, although hindering membrane passage, can either reduce or enhance partition in phospholipids, depending on analyte lipophilicity.