In this study, a zwitterionic hydrogels, poly(sufobetaine) methacrylate [Poly(SBMA)], was synthesized and evaluated for their applications as tissue engineering scaffolds. The cytotoxticity and endotoxicity were tested. The non-specific protein resistance was compared with those of poly(HEMA) hydrogels. In vitro tests showed that poly(SBMA) hydrogel could inhibit cell growth. In vivo implants of poly(SBMA) were also histologically evaluated and compared for the vascularity and foreign body reaction. Poly(SBMA) hydrogels are responsive to ionic strength and PH for their protein resistance, swelling and mechanical properties. Based on the responsive properties, the mechanical properties of the hydrogel were improved by a novel swelling-penetrating method.