The antifouling property of exogenous materials is vital for their in vivo applications. hi this work, dissipative particle dynamics simulations are performed to study the self-assembled morphologies of two copolymer systems containing poly(ethylene glycol) (PEG) and poly(carboxybetaine) (PCB) in aqueous solutions. Effects of polymer composition and polymer concentration on the self-assembled structures of the two copolymers (PLA-PEG and PLA-PCB) are investigated, respectively [PLA represents poly(lactic acid)]. Results show that whatever the copolymer composition is, PLA-PEG systems will self assemble into core-shell structures, whereas onion-like and vesicle structures are also found for the PLA-PCB systems. Different morphologies are obtained at different polymer concentrations in both copolymer systems. Simulation results demonstrate that PCB is more stable than PEG in maintaining self-assembled spherical structures of copolymer systems because PLA-PEG forms dumbbell-like structures whereas PLA-PCB is spherical under the same polymer concentration. Although both copolymer systems can self-assemble into core-shell nanoparticles when the block ratio of PLA:PEG or PLA:PCB is 80:20, the core-shell structures of the nanoparticles are quite different. The shell layers formed by PEG in PLA-PEG nanoparticles are inhomogeneous in size because of the amphiphilicity of PEG, whereas the shell layers in PLA-PCB nanoparticles are homogenous because of the strong hydrophilicity of the zwitterionic PCB polymer block.