Effect of gas–liquid flow pattern on the performance of air-sparged cross-flow microfiltration of yeast suspension is studied. The pseudo-steady filtration flux and the cake properties under various operating conditions are measured and discussed. The shear stress acting on the membrane surface and the critical condition for particle deposition are analyzed theoretically based on hydrodynamic models. The cake mass is markedly reduced by increasing the wall shear stress. However, the average specific cake filtration resistance increases with increasing the wall shear stress due to more compact cake structure. The increase in the average specific filtration resistance of cake due to air-sparging is more significant in bubbly flows. Consequently, the filtration flux will be increased by air-sparging due to the cake reduction in slug flow microfiltration. However, a contrary result is obtained for bubbly flows due to the drastic increase in the average specific filtration resistance of cake. Therefore, a microfiltration operating under slug flow is more effective to enhance the filtration flux by air-sparging. In addition, the proposed model provides a method to quantitatively relate the filtration flux to operating parameters. The relationships are also strongly dependent on the gas–liquid flow pattern.