Poly(2-methacryloyloxyethyl phosphorylcholine) (pMPC), when end-tethered to surfaces by the adsorption of copolymeric cationic segments, forms adsorbed layers that substantially reduce protein adsorption. This study examined variations in the molecular architecture of copolymers containing cationic poly(trimethylammonium ethyl methacrylate (pTMAEMA) anchor blocks that adsorbed strongly to negative surfaces. With appropriate copolymer design, the pTMAEMA blocks were shielded, by pMPC tethers, from solution-phase proteins. The most protein-resistant copolymer layers, eliminating fibrinogen and lysozyme adsorption within detectible limits of 0.01 mg/m(2), had metrics (the amount of pMPC at the surface and the reduced tether footprint) consistent with the formation of an interfacial polymer brush. The p(TMAEMA-b-MPC) copolymer layers substantially outperformed the protein resistance of surface-polymerized pMPC layers when compared on a per-polyzwitterion-mass basis or on the basis of the scaled tether area. Additionally, p(TMAEMA-b-MPC) copolymer layers offered advantages over the much-studied cationically anchored poly(ethylene glycol) (PEG) graft copolymer system, which forms PEG brushes by the adsorption of a poly L-lysine (PLL) backbone. Although the optimized p(TMAEMA-b-MPC) and PLL-PEG copolymers were similarly fibrinogen-resistant, the cationic protein lysozyme was repelled by pMPC but adhered to the PEG brush via PEG lysozyme attractions. Additionally, the adsorbed p(TMAEMA-b-MPC) copolymers were not, displaced by poly L-lysine homopolymers, which completely displaced the PLL-PEG copolymer to expose a protein-adhesive surface. Thus, the p(TMAEMA-b-MPC) copolymer system comprises a scalable means to produce protein-repellent surfaces, free of the complexities of surface-initiated polymerization and with the advantages of polyzwitterions.