Calcium phosphate cements have been recently introduced for use in craniofacial reconstruction. In the clinical setting, however, pulsations of the underlying brain and dura may interfere with the crystallization of these cements, thereby rendering their use in cranioplasty problematic. To circumvent such problems, many clinicians have interposed synthetic resorbable plates or mesh between the dura and the cement. At the present time, however, little is known about the influence of such materials or their breakdown products on the fate of calcium phosphate cements. The specific aim of this project was to evaluate the biocompatibility, osteoconductivity, and remodeling capacity of a calcium phosphate cement after implantation into experimental calvarial defects when combined with a resorbable mesh underlay. Four 10-mm diameter full-thickness calvarial defects (two frontal, two parietal) were created in each of six 3-week-old Yorkshire pigs. The defects were treated as follows: 1) empty control, 2) macroporous polylactic acid (70/30 L/DL polylactic acid [PLA]) mesh, 3) Norian CRS calcium phosphate cement, and 4) Norian CRS over PLA mesh underlay. Animals were divided into two groups. Half of the animals were killed 30 days after surgery, and half were killed 180 days after surgery, and the graft recipient sites were examined histologically. At 30 days, minimal bone ingrowth was observed in untreated calvarial defects or in those that were treated with PLA plates alone. Defects treated with the cement alone demonstrated a modest amount of new woven bone deposition, primarily at the periphery of the implants. Defects treated with calcium phosphate cement over PLA mesh underlays were characterized by remodeling and woven bone deposition at 30 days, with complete or near-complete osseous bridging of the ectocranial implant surfaces. Progressive bone ingrowth was noted in all defects at 180 days, with near-complete replacement of all Norian CRS implants by host bone. The PLA mesh remained incompletely resorbed at 180 days. No inflammatory response to the implants was observed at either time point. Calcium phosphate cement may be safely used for craniofacial reconstruction in the presence of PLA implants without compromise to its biocompatibility, osteoconductivity, or remodeling capacity.