A two-dimensional lattice model that highlights the hydrophobic interaction between protein and micro-filtration（MF）membrane was presented for dynamic Monte Carlo simulation of the membrane fouling process. The effect of membrane pore size，protein concentration and structure on membrane fouling was examined. It was shown that the MF process could be divided into three stages according to the changes in the trans-membrane flux，i. e. ，rapid declining，slow declining and quasi-steady-state. For the MF membrane with a small pore size，cake resistance became dominating while the pore resistance contributed less to the overall filtration resistance along with the filtration process，while the filtration using the membrane with a large pore size was dominated by the pore resistance. The increase of protein concentration accelerated the shift of the dominating role from pore resistance to cake resistance. The hydrophobic interaction between membrane and protein may lead to the unfolding of protein，the enhancement of the irreversible multi-layer adsorption onto membrane surface，and consequently，the reduction of trans-membrane flux. The enhancement of protein structure characterized [JP+3]by hydrophobic core may repress the adsorption and this could be accomplished by choosing an appropriate solution. The simulation results agreed well with both experimental investigation and theoretical models reported elsewhere. The molecular insight of the MF process provided by the above simulation is helpful for the optimization of the MF process and design of new MF membrane.