This work introduces a thermally stable zwitterionic structure able to withstand steam sterilization as a general antifouling medical device interface. The sulfobetaine methacrylate (SBMA) monomer and its polymer form are among the most widely used zwitterionic materials. They are easy to synthesize and have good antifouling properties. However, they partially lose their properties after steam sterilization, a common procedure used to sterilize biomedical interfaces. In this study, ultrahigh-performance liquid chromatography/mass spectrometry (UHPLC-MS) was used to analyze and discuss the molecular structure of SBMA before and after a steam sterilization procedure, and a strategy to address the thermal stability issue proposed, using sulfobetaine methacrylamide (SBAA) instead of SBMA. Interestingly, it was found that the chemical structure of SBAA material can withstand the medical sterilization process at 121 °C while maintaining good antifouling properties, tested with proteins (fibrinogen), bacteria (Escherichia coli), and whole blood. On the other hand, SBMA gels failed at maintaining their excellent antifouling properties after sterilization. This study suggests that the SBAA structure can be used to replace SBMA in the bioinert interface of sterilizable medical devices, such as rayon fiber membranes used for disease control.