Purpose: The purpose of this study was to investigate the influence of cortical perforation on angiogenesis and osteogenesis following guided bone regeneration using synthetic bone substitutes in rabbit cranial defects. Materials and Methods: The right and left sides of the calvaria were exposed in 11 rabbits. In each rabbit, two custom-made titanium domes were placed on either side of the midline. In experimental sites, the cortical surface inside the boundary of one of the two circular slits was then mechanically perforated five times with a round bur; in control sites, this was left intact. All sites received beta-tricalcium phosphate. The animals were sacrificed at 2, 4, and 8 weeks. Biopsy samples were examined histomorphometrically by light microscopy, and the expression of vascular endothelial growth factor (VEGF) and osteocalcin (OC) was determined immunohistochemically. Results: The percent area of newly formed bone was significantly higher in the experimental group than in the control group 2 weeks after surgery. Marrow cells reached the normal rabbit calvarial bone more rapidly in experimental sites than in control sites. Immunostaining intensity and the percentage of positively stained cells for VEGF were greater in the experimental group than in the control group at 2 weeks after surgery. At 4 weeks, immunostaining intensity and the percentage of positively stained cells for OC were greater in the experimental group than in the control group. However, there were no significant differences between the experimental and control groups in immunohistochemical findings for VEGF and OC. Conclusions: The results of this study suggest that cortical perforation of the receptor bone may improve angiogenesis in bone grafts and increase the amount of newly formed bone in grafted areas, especially in the early bony healing phase. Further studies in larger samples are needed to confirm these results. Keywords: beta-tricalcium phosphate, cortical perforation, osteocalcin, vascular endothelial growth factor