The influence of ionic sites on the selectivities of ionophore-based ion-selective electrodes (ISEs) is described on the basis of a phase boundary potential model. The discussion presented here is significantly more general than previous ones. It is formulated for primary and interfering ions of any charges and it is valid for ISEs based on electrically charged or neutral ionophores. Furthermore, it also applies to membranes that contain more than one type of complex of the primary or interfering ion. It has been believed thus far that only ionic sites of the same charge sign as the primary ion improve the selectivities of ISEs based on charged ionophores. However, it is shown here that the charge sign of the ionic sites that give the highest potentiometric selectivities depends on the charge number of the primary and interfering ions and on the stoichiometry of their complexes with the ionophore. The validity of our model was confirmed experimentally with three ISEs based on different charged ionophores. ISEs based on lasalocid or 1- (N,N-dicyclohexylcarbamoyl)-2-(N,N-dioctadecylcarbamoyl)ethylphosphonic acid monomethyl ester (ETH 5639) as the ionophore responded selectively to Sr2+ or Mg2+, respectively, and discriminated well against other alkaline earth cations when their membranes contained anionic sites. These two electrodes are the first examples of ISEs based on charged ionophores for which maximum selectivities are obtained with membranes containing ionic sites with a charge sign opposite to that of the primary ion. On the other hand, the experimental F- selectivities of membranes based on oxo(5,10,15,20- tetraphenylporphyrinato)molybdenum(V) improved gradually when the concentration of anionic sites was increased from 0 to 75 mol %. The selectivity-modifying influence of ionic sites for these three types of ISEs can be explained by considering the different stabilities of the 1:2 ion- ionophore complexes of the primary and of the interfering ions.