The cross-flow microfiltration of fine particle/macromolecule binary suspension is analyzed and modeled in this study. The filtration rate, the cake thickness and the rejection of macromolecules can be estimated from the operating variables by modeling the cake formation, the concentration polarization and the penetration of macromolecules through the filter cake. Based on the force balance model, the thickness of the filter cake formed by fine particles can be related to the operating conditions. The formed cake plays the major roles on the filtration resistances and on the rejection of macromolecules. A reversible concentration polarization layer is constructed with the macromolecules near the cake surface. The concentration profile in this layer can be calculated using the mass transfer equation once the mass transfer coefficient is obtained from the analogy analysis. The standard capture equation for depth filtration is adopted to simulate the retention and the penetration of macromolecules in the filter cake. Experiments are carried out using the binary suspensions prepared by polymethyl methacrylate (PMMA) particles and the Dextran macromolecules. The filtration rates, the rejection of Dextran and the cake properties under various operating conditions are measured and discussed. The predicted values using the proposed models agree fairly well with the experimental data under various operating conditions.