Autologous bone grafts are the preferred material for craniofacial reconstruction, but such procedures lead to increased operative time and bleeding, donor site morbidity, and graft resorption. The efficacy of expanded-polytetrafluoroethylene (e-PTFE) sheets to increase bone regeneration and remodeling in cranial defects using a rabbit model was evaluated by mechanical testing. New Zealand white rabbits were divided into 3 groups and sacrificed 6 months after surgery. In the Split Table group, (n = 16), a bilateral bone defect was created on the outer table of the parietal bones. In the Full Table group, (n = 16), a bilateral defect was created through both the inner and outer table of the cranium. The control group, (n = 10) was subjected to a sham operation. Indentation testing was performed to determine the stiffness of newly formed bone in and around the defect. Near the center of the defect, Split Table defects repaired with e-PTFE resulted in significantly stiffer bone than regenerated control bone. The Full Table defects repaired with e-PTFE also resulted in bone significantly stiffer than control regenerated bone around the central region of the defect. The data supports the hypothesis that e-PTFE improves the repair of cranial defects in a rabbit model. It is surmised that the porosity of the e-PTFE provides a stable scaffold for migration of tissue regenerating cells, which may be preferentially localized near the cranial suture lines. This porosity may also provide a barrier to fibrous tissue regenerating cells.