Particle deposition in spacer-filled membrane modules is investigated using a computational fluid dynamic (CFD) technique. The flow field and particle transport in the channels with permeable membrane surfaces are calculated using the commercial available CFD software FLUENT®. A scheme similar to the Eulerian–Lagrangian numerical method is adopted for the two-phase flow simulation. Particle transport in three spacer-filled channel configurations is analyzed by considering fluid drag, body force, and lift force exerted on the particles. Feed velocity, permeation flux, and spacer arrangement effects on particle deposition are discussed comprehensively. Based on conclusive preliminary study results, multi-phase flow simulation can provide microscopic understanding of the fouling mechanism in the spacer-filled channel and prove to be a powerful tool to aid in membrane module design.