Natural waters and wastewater contain both colloidal materials and dissolved organic matter. Although extensive research has been done on colloidal fouling and organic fouling processes separately and their mechanisms are relatively well understood, little is known about the combined fouling process during filtration of a complex suspension containing both types of foulants. Using a combination of experimental measurement and computational modeling, this research explores the physicochemical mechanisms involved in the combined fouling process. In particular, the two major mechanisms investigated were hindered back diffusion due to the high concentration of each foulant near the membrane surface and changes in colloid deposition behavior due to adsorption of macromolecules onto the colloid surface. The impact on the characteristics of the membrane due to macromolecule adsorption is also considered. The model incorporates the hindered back diffusion mechanism by calculating the local fluid viscosity in the concentration polarization layer and modifying the diffusion and flow accordingly. Fouling experiments in a cross-flow filtration system using nanofiltration membranes were conducted with colloidal silica and two model organic foulants: a non-interacting macromolecule, Dextran, and an interacting macromolecule, bovine serum albumin (BSA). The model organic foulants were chosen for their respective adsorptive properties in order to isolate the effects of hindered back diffusion from the effects of macromolecule-mediated colloid deposition. Model predictions are compared to experimental results as well as existing concentration polarization/fouling models.