The aim of this work was the formulation of a theoretical multi-scale model simulating the membrane separation of proteins. The proposed approach integrated the knowledge about separation process, as attained at different lengths and timescales. The fouling progress, as determined by protein layers deposited on the membrane surface, and the permeate flux decay of dead-end ultrafiltration were predicted without resorting to adjustable parameters. With reference to Bovine Serum Albumin (BSA) the electrostatic surface charges were calculated by accurate quantum mechanics approaches, along with the contact molecular surface and the BSA effective diameter. These quantities were exploited to estimate the BSA surface potential necessary to formulate, at a microscopic scale, a balance of the forces acting on each BSA particle. The additional resistance clue to the accumulated protein layers was then calculated, thus allowing the transition to a macroscopic scale. A transport model describing the unsteady-state mass transfer of BSA was eventually formulated to predict the behavior of dead-end UP process as a function of the operating conditions. The predictions of the proposed multi-scale model were compared with a set of experimental data collected filtering a BSA aqueous solution through a polyethersulfone ultrafiltration membrane. (C) 2013 Elsevier B.V. All rights reserved.