Mathematical modeling of flux decline during filtration plays an important role in both sizing membrane systems and in the understanding of membrane fouling. Protein fouling is traditionally modeled using one of three classical fouling mechanisms: pore blockage, pore constriction or cake filtration. Here, we have developed a mathematical model to describe flux decline behavior during microfiltration accounting for all three classical fouling mechanisms. Pore constriction was assumed to first reduce the size of internal pores. Pore blockage then occurs at the top of the membrane, preventing further fouling to the interior structure. Finally the foulants at the top of the membrane form a cake, which controls the late stages of the filtration. The model prediction shows excellent agreement with experimental data for 0.25 mu m polystyrene microspheres filtered through 0.22 mu m Isopore membranes (where pore constriction is expected to be minimal) as well as non-aggregated bovine serum albumin solution through hydrophobic Durapore membranes (where pore constriction is expected to dominate). The effects of different fouling mechanisms on the flux decline were characterized by the ratio of characteristic fouling times of the different mechanisms. In this way the model can provide additional insights into the relative importance of different fouling mechanisms as compared to an analysis by a single mechanism model or by derivative plots, and it can be used to provide important insights into the flux decline characteristics. (c) 2006 Elsevier B.V. All rights reserved.