The organization principles of a new type of sensors were developed whose analytical signal is the Donnan potential at the ion-exchange polymer/test solution interface (PD-sensors) for the determination of organic and inorganic electrolytes in multicomponent aqueous solutions. It was found that the cross sensitivity of PD-sensors based on perfluorinated, sulfonated cation-exchange polymers (PSPs) in the initial inorganic forms depends on the potential-determining reactions of protolysis and ion exchange at the PSP/multicomponent test solution interface. The effects of the hydrophilicity, moisture capacity, and ionic form of the ion-exchange polymer on PD-sensor sensitivity were investigated. It was found that treatment of PSP with ethylene glycol at the glass-transition temperature of the polymer makes it possible to obtain modified PSPs in organic forms, which differ from the initial materials by a larger concentration of dissociated counterions, and thus lead to enhanced PD-sensor response and sensitivity to an appropriate organic component. Potentiometric multisensor systems including cross-sensitive PD-sensors, ion-selective electrodes (ISEs), and algorithms for the processing of multidimensional data for the quantitative determination of lysine, novocaine, lidocaine, thiamine, pyridoxine, nicotinic acid, and alkali and alkaline earth metal cations in multicomponent solutions were developed.