Despite their excellent fouling resistance, solubility issues of zwitterionic copolymers limit their use in membrane surface modifications by coating or blending. This work presents an innovative method to form a random copolymer of polystyrene (PS) and poly(sulfobetaine methacrylate) (PSBMA), and modify in the same time poly (vinylidene fluoride) (PVDF) membranes. As the polymer is formed, it is self-deposited on the membrane. Hence, a solvent for PS-r-PSBMA does not have to be found to coat the membranes. The first part of this work consisted in optimizing the reaction conditions, by varying the SBMA to styrene monomer ratio, the reaction time and the solid content in the reactive mixture. A 50/50 monomer ratio, a reaction time of 5 h and a total solid content of 5 wt% were found to lead to a water contact angle at equilibrium close to 0 and to a reduction of 90% of fibrinogen adsorption. Using the optimized membrane, efficient resistant to fouling in complex medium was achieved, as fibrinogen from a platelet-poor-plasma solution was reduced by almost 80%, compared with the unmodified membrane. Almost complete resistance to platelets, leukocytes, erythrocytes, whole blood and E. coli adhesion were achieved. Furthermore, a flux recovery ratio (FRR) of 93% was obtained after incubating the membrane in a platelet-poor-plasma solution, outperforming a hydrophilic commercial PVDF membrane (FRR = 70%). Although further optimization of the process needs to be done, the method presented is promising for facile, stable and cost-effective surface zwitterionization of membranes.