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Zwitterionic polymers are widely recognized for their exceptional antifouling performance; however, integrating zwitterionic functionality into polyurethane while retaining mechanical robustness and processability remains a significant challenge. Addressing this gap, we introduce a versatile design strategy for synthesizing zwitterionic polyurethanes that integrate both zwitterionic diol and triol precursors, enabling long-term antifouling performance and tunable physical properties. We report the synthesis of a new class of poly(carboxybetaine hexamethylene urethane) (PCBHU) prepared through step-growth polymerization of carboxybetaine (CB)-based diols/triols and aliphatic diisocyanates, followed by controlled ester hydrolysis to generate zwitterionic groups along the polymer backbone. The formation of densely hydrated CB moieties establishes a strongly bound hydration layer that governs the antifouling behavior. The resulting materials exhibit excellent thermal stability, with degradation temperatures above 200 °C, and well-defined thermal transitions characterized by TGA and DSC. By varying the soft-to-hard-segment ratio, we achieved precise control over mechanical properties and water uptake, revealing clear structure-property relationships within this zwitterionic PU platform. Importantly, the PCBHUs markedly suppress nonspecific protein adsorption, mammalian cell adhesion, bacterial attachment, and biofilm formation, demonstrating durable antifouling performance far superior to conventional polyurethanes. The synthesis route is simple, scalable, and compatible with existing PU manufacturing, enabling these PCBHUs to serve as drop-in replacements for commercial polyurethane lacking antifouling functionality. This strategy provides a practical and broadly applicable approach for endowing polyurethane-based biomaterials and medical devices with long-lasting antifouling properties.