Linear poly(N-hydroxyethylacrylamide) (PHEAA) is regarded as one of the most promising antifouling materials because of its excellent antifouling properties and good hemocompatibility. However, the antifouling performance of topological PHEAAs remains largely unknown. Herein, the preparation of antifouling surfaces based on a tadpole-shaped PHEAA coating is reported for the first time, and how the tadpole-shaped PHEAA architecture affects antifouling performance is investigated. It is shown that the tadpole-shaped PHEAA-modified surfaces exhibit better antifouling performance than linear copolymer precursor-modified surfaces with identical molar masses and chemical compositions. This may be primarily attributed to the presence of cyclic PHEAA head chain segments in the tadpole-shaped PHEAA copolymer, and the absence of interchain entanglements can facilitate the formation of smoother and densely packed grafts, which result in better antifouling properties.