The behavior of mixtures of inorganic nanoparticles and natural organic matter (NOM) during nanofiltration (NF) was investigated in a lab-scale crossflow filtration system to identify how interactions between these foulants influenced deposition and membrane performance in terms of NOM and salt selectivity. NOM selectivity was reduced substantially when the colloid concentration was sufficient to produce a thick deposited colloidal cake, as a result of enhanced concentration polarization phenomena. This increased the concentration and hence the driving force for NOM. It also increased salt concentration, which screened NOM charge. In addition to reducing the double layer thickness, charge screening has also been shown to reduce NOM effective size, increasing the membrane permeation coefficient. On the other hand, the presence of NOM in the cake layer matrix substantially attenuated the enhancement of salt concentration polarization. A multilayer solute transport model was applied to describe these phenomena and simulate solute selectivity for both NOM and salt in colloid-NOM mixtures. Good agreement of model calculations with experimental data was observed. According to this model, the properties of the first deposited colloidal cake layer is critical in determining the quality of the permeate product in terms of NOM or salt retention.