Perfluorosulfonate ionomer (PFSI) membranes can be used to protect biosensors in biological environment. Perfluorocarboxylate ionomer (PFCI) has similar structure to PFSI, and is thus expected to be applicable in vivo. In this study, biocompatibility and anti-cracking performance of PFCI membranes were first investigated. Among various kinds of PFCI membranes, the Na+-type exhibited best blood compatibility, as evidenced by the human platelet adhesion and hemolysis rate experiments. When cultured on Na+-type PFCI membranes, endothelial cells spread and proliferated to colonize the entire surface, indicating good cell adhesion activity of the membranes. The Na+-type membranes were also subcutaneously implanted into guinea pigs, whose incisions were healed after operation without significant rejection phenomenon. After incubation in cell culture medium for 12 weeks, PFCI membranes kept intact only with trace amount of calcium phosphate deposition. XRD and SAXS results demonstrated that PFCI membranes possessed higher crystallinity and smaller ion cluster size than PFSI membranes, thereby endowing the membranes with much better anti-cracking performance. The excellent biocompatibility and anti-cracking performance of Na+-type PFCI membranes make them promising implantable biomaterials and protective layers in biosensors.