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Background: Expanded polytetrafluoroethylene (ePTFE) and silicone are safe and relatively biocompatible materials., Objective: To compare, using multiple histologic parameters, the tissue response to a standard silicone soft tissue implant with the response to a modified ePTFE implant. The modified form of ePTFE is reinforced with fluorinated ethylene propylene (FEPRePTFE), which provides increased pliability and material integrity., Methods: The implants were placed into a subperiosteal pocket over the skull of adult New Zealand white rabbits. At 7, 30, and 90 days after implantation, en bloc tissue specimens, including skin, implants, surrounding soft tissue, and underlying bone were harvested for gross and histologic evaluation., Outcome Measures: The tissue response to the implants was assessed with respect to the number of foreign body giant cells present, the thickness of the fibrous capsule, and the general inflammatory response (n = 6 for each implant at each evaluation period)., Results: There were no cases of rejection, extrusion, or infection. The silicone implants elicited a significantly thicker capsule and less neovascularization (P<.05)., Conclusion: The FEPRePTFE demonstrated a favorable tissue response when compared with silicone, particularly in regard to capsule thickness and vascular ingrowth.