This publication presents a novel ISFET-based measurement concept for the determination of the zeta potential, which is known to be an efficient method for the detection of protein accumulations onto surfaces. The basic set-up consists of two monolithically integrated ISFET sensors arranged in a serial flow configuration together with a precoated fused silica capillary, which provides the reactive surface for the protein detection. In comparison with the state of the art, this novel biosensor system is characterized by a small size, an extremely low reagent consumption, a simple fluidic concept, a short analysis time, and a very effective noise suppression due to the differential ISFET set-up. In the following, an overview is given over the theoretical background of the measurement principle. In order to get deeper insight into the theoretical background of the measurement principle, a simulation model was developed which is based on the site-binding theory and takes into account the different proton dissociation equilibria of the surface groups as well as the influence of monovalent electrolyte ions. A quasi-Newton iteration after Broyden was used for the numerical solution of the formulated equation system. For an experimental confirmation of the simulation results, the calculated zeta potential vs. pH curves were compared with measured data for various modifications of the fused silica capillaries (in untreated state, after a hydrothermal activation, and after the deposition of several silanes) and it could be shown, that the chosen physical model represents a satifactory theoretical basis for the description of the occuring surface effects. Measurements before and after a covalent coupling of the model analyte lysozyme were performed in order to demonstrate the feasibility of an immunosensor based on the measurement of the streaming potential and showed a significant shift of the zeta potential vs. pH curves.