Fouling is one of the most critical aspects of membrane technology and is strongly influenced by natural water characteristics.This studyfocuses on a mechanistic understanding of the impact of interactions between natural organic matter (NOM) and particles on fouling. The model substances used were humic acid, alginate (polysaccharide), and kaolinite. NOM-kaolinite adsorption experiments, particle characterization, and dead-end ultrafiltration (UF) batch experiments were performed. The adsorption experiments indicated particle stabilization at low NOM equilibrium concentrations, whereas calcium induced significant aggregation, especially with alginate. UF experiments implicated a synergistic fouling effect of particle-NOM combinations, which was greatly reduced by calcium. Moreover, irreversible NOM fouling was only prevented by particles in the presence of calcium. On the basis of our results, we present a mechanistic model suggesting that synergistic fouling effects occur due to particle stabilization by NOM adsorption, especially shown for HA, and antagonistic effects due to particle destabilization by calcium. However, synergistic fouling can also be based on sterical interferences between larger NOM in the form of polysaccharides and particles during simultaneous pore blocking and cake formation. A heterogeneous NOM-particle fouling layer is ultimately formed with membrane associations dominated by NOM. The combined fouling is conclusively determined bythe type of NOM, its specific fouling mechanisms, and its particle interactions prior to and during the filtration process.