The cell membrane establishes an important paradigm for the molecular engineering of coatings for implantable devices because of its intrinsic biocompatibility and ability to act as a template for the assembly of diverse membrane-associated macromolecules. A stabilized membrane-mimetic film was assembled on alginate/Ca(2+) hydrogel microcapsules by in situ polymerization of an acrylate functionalized phospholipid. The phospholipid monomer was prepared as unilamellar vesicles and fused onto octadecyl chains that were components of an amphiphilic terpolymer anchored onto a polyelectrolyte multilayer (PEM) by electrostatic interactions. Microcapsules coated with a membrane-mimetic film were implanted into the peritoneal cavity of C57BL/6 mice, and the short-term biostability and biocompatibility of membrane-mimetic films assembled on two different alginate/poly(l-lysine) PEM cushions were compared. The nature of the underlying PEM support had a profound impact on the biocompatibility of the membrane-mimetic film, as the percentage of retrieved microcapsules completely overgrown with host cells shifted from 66+/-5.9% to less than 1% when modifications to the PEM were made. When assembled on the appropriate PEM support, biocompatibility of membrane-mimetic-coated microspheres was high wherein 87.5+/-5.7% of the implanted microspheres were retrieved 4 weeks after implantation and 92.6+/-6.4% of the retrieved capsules were free of cell adhesion or fibrotic overgrowth. Finally, 4 weeks after implantation, microspheres coated with a Texas red-labeled membrane-mimetic film were imaged with confocal microscopy and exhibited a uniform film around the periphery of the implant, indicating a high degree of film biostability. Hence, membrane-mimetic films provide a new route for generating robust, biocompatible, and biochemically heterogeneous coatings for implantable devices through molecular self-assembly.