Novel polyurethanes with zwitterionic sulfobetaines, termed PUR-APS, were designed and synthesized by chain-extension of biodegradable poly(ε-caprolactone) containing N,N′-bis (2-hydroxyethyl) methylamine ammonium propane sulfonate (PCL-APS) with hexamethylene diisocyanate (HDI). The bulk properties of polymers were characterized by nuclear magnetic resonance spectrum (NMR), Fourier transform infrared spectroscopy (FTIR), gel permeation chromatograph (GPC), and differential scanning calorimetry (DSC). Results showed that the polymers were successfully synthesized. Water contact angles (WCAs) and X-ray photoelectron spectroscopy (XPS) revealed that molecular chains of the polymers rearranged after soaking in water. The amount of protein adsorption, determined by bicinchoninic acid (BCA) assay, was less than 300 ng/cm2 and decreased after hydration. The blood compatibility of the polymers was evaluated by the degree of hemolytic and activated partial thromboplastic time (APTT) and prothrombin time (PT). Results indicated that PUR-APS polymers had good blood compatibility. Therefore, polyurethanes containing sulfobetaines have a great potential for biomedical application. © 2012 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 101A: 909–918, 2013.