Biofouling on silicone implants causes serious complications such as fibrotic encapsulation, bacterial infection, and implant failure. Here we report the development of antifouling, antibacterial silicones through covalent grafting with a cell-membrane-inspired zwitterionic gel layer composed of 2-methacryolyl phosphorylcholine (MPC). To investigate how substrate properties influence cell adhesion, we cultured human-blood-derived macrophages and Escherichia coli on poly(dimethylsiloxane) (PDMS) and MPC gel surfaces with a range of 0.5-50 kPa in stiffness. Cells attach to glass, tissue culture polystyrene, and PDMS surfaces, but they fail to form stable adhesions on MPC gel surfaces due to their superhydrophilicity and resistance to biofouling. Cytokine secretion assays confirm that MPC gels have a much lower potential to trigger proinflammatory macrophage activation than PDMS. Finally, modification of the PDMS surface with a long-term stable hydrogel layer was achieved by the surface-initiated atom-transfer radical polymerization (SI-ATRP) of MPC and confirmed by the decrease in contact angle from 110 to 20° and the >70% decrease in the attachment of macrophages and bacteria. This study provides new insights into the design of antifouling and antibacterial interfaces to improve the long-term biocompatibility of medical implants.