The in vivo tissue response to a newly developed fiber-reinforced calcium phosphate cement (CPC) formulation was assessed using a well-established rabbit calvarial defect model. Bilateral subcritical sized (8-mm diameter) defects were surgically created in the parietal bones of each rabbit (a total of 48 rabbits), and randomized to be filled with either the new fiber-reinforced formulation, a conventional CPC (positive control), or left unfilled (negative control). The implant sites were subsequently retrieved after 12, 24, and 52 weeks postsurgery. Each specimen, including the parietal bone craniotomy and underlying brain, were recovered at necropsy and the tissue responses were assessed by histology. The resulting histological slides indicated that there was no evidence of severe inflammatory responses or osteolysis. The data showed new dural and pericranial bone formation along the implants, as well as excellent bone-to-implant interfaces in all of the CPC-filled defects. These results suggest that the biologic response to the new fiber-reinforced CPC formulations and conventional nonreinforced CPC are very similar, and both demonstrate excellent biocompatibility as well as an overall osteophylic response.