Objectives: Calvarial defects must be closed for either cosmetic reasons or for protection of the calvarial contents. We aimed to assess whether Cortoss™, a biocompatible synthetic cortical bone void filler, can provide satisfactory osteointegration in cranial defects. Methods: Twenty New Zealand white adult rabbits were divided into 4 groups: craniectomy (n = 6), cranioplasty (n = 6), sham (n = 6) and control (n = 2) groups. Treatment for each group was as follows: craniectomy group had calvarial defects that were left empty; the cranioplasty group the defects were reconstructed with Cortoss™; the sham group had only a skin incision and no defect; and in the control group no surgery was performed. All the animals were sacrificed 6 months after the procedures and the materials were examined histopathologically and radiologically in order to assess osteointegration of Cortoss™. Results: Radiological examination demonstrated almost complete apposition of the bone to Cortoss™ without any defect or sutures and the cosmetic outcomes were satisfactory. Radiological findings were supported by the histopathologic examinations which revealed that osteointegration had been completed without any fibrous band formation surrounding the Cortoss™ implant. Conclusion: Cortoss™ leads to significant osteointegration at 24 weeks in rabbit calvarial defects. The results of this in vivo study suggest that Cortoss™ may be considered a safe and effective material for the reconstruction of calvarial defects.