Two types of zwitterionic polymer-modified magnetic nanoparticles (NPs) are fabricated by conjugating pSBMA onto PEI-precoated NPs via either a one-step method (IS NPs) or two-step method (2S NPs). For both methods, divinyl sulfone is used as the linker molecule. Although 1S NPs were capable of resisting both IgG and BSA, 2S NPs exhibited specificity toward IgG adsorption in complex biological fluids, e.g., in a mixture of serums and IgG. The moderate interactions (K-d approximate to 1.2 mu M) between IgG and 2S NPs are 3 orders of magnitude lower than IgG binding with protein A (K-d 10 nM). Through complementary characterizations and analyses, we rationalize that the surface developed herein with IgG specificity contains two key components: polyzwitterions with a short chain length and sulfone groups with a high density.