Although widely used in blood-contacting devices, polypropylene (PP) membranes are prone to biofouling by plasma proteins and blood cells. The present study explores the effect of a surface zwitterionization process on the improvement of the biofouling resistance of PP membranes for leukocyte reduction fillers. The modification strategy consists in forming an interpenetrating network of poly(glycidyl methacrylate-co-sulfobetaine methacrylate) (poly(GMA-co-SBMA) around the fibers of coated PP membranes, using a cross-linking agent ethyle-nediamine (EDA). It is shown that with EDA, a range of poly(GMA-co-SBMA) concentration (1-5 mg/mL) leads to a 0 degrees-water contact angle and high hydration of the networks without affecting the intrinsic porous structure of the material. Besides, the related membranes show excellent resistance to biofouling by Escherichia coll., fibrinogen, leukocytes, erythrocytes, thrombocytes and cells from whole blood with reductions in adsorption of 97%, 86%, 90%, 95%, 97% and 91%, respectively, compared to unmodified PP. Used in whole blood filtration, it is demonstrated that in the best conditions (5 mg/mL copolymer, with EDA), leukocytes can be efficiently removed (> 99.99%) without altering the erythrocytes concentration in the permeate, and that leukodepletion is more efficient than that measured with a commercial hydrophilic PP blood filter (about 50% retention). Physical retention of leukocytes is only efficient if the membrane material is anti-biofouling, and so, does not interact with other blood components able to trigger leukocyte attachment/deformation.