A higher surface density of poly(ethylene glycol) (PEG) on polymeric micelles enhances their stability in serum, leading to improved plasma circulation. To obtain fundamental, mechanistic understanding of the PEG effect associated with polymeric architecture/configuration, we have synthesized PEGylated dendron-based copolymers (PDCs) and linear block copolymers (LBCs) with similar molecular weights. These copolymers formed dendron (hyperbranched) and linear micelles, respectively, which were compared in terms of their stabilities in serum, micelle-serum protein interactions, and in vivo biodistributions. Overall, the dendron micelles exhibited a better serum stability (longer half-life) and thus a slower release profile than the linear micelles. Fluorescence quenching assays and molecular dynamics (MD) simulations revealed that the high serum stability of the dendron micelles can be attributed to reduced micelle-serum protein interactions, owing to their dendritic, dense PEG outer shell. These results provide an important design cue for various polymeric micelles and nanoparticles.