PepGen P-15 is a combination natural anorganic bovine-derived hydroxyapatite matrix (ABM) coupled with a synthetic cell-binding peptide (P-15). This material has been reported to enhance bone formation in periodontal osseous defects. The aim of this study was to assess the effect of ABM/P-15 on the healing of cortical bone defects in rabbits. Five New Zealand rabbits were used. Two 8-mm bone defects were created in each tibia. Eight defects were filled with PepGen P-15, 8 defects with PepGen P-15 Flow, and 4 defects were used as a control group. A total of 20 defects were created. All rabbits were killed at 4 weeks. Block sections containing the defects were retrieved and the specimens processed for light microscopy examination. Newly formed bone was present in both test groups, whereas, in the control-group, only a scarce quantity of newly formed bone was present and the cortical defects had not been filled by the regenerated bone. Statistical evaluation showed that there were statistically significant differences between control sites and sites treated with P-15 and P-15 Flow (P = 0.0001), and also between sites treated with P-15 and P-15 Flow (P = 0.0001), respectively. No acute inflammatory infiltrate cells were visible in both of these groups. Both PepGen P-15 and PepGen P-15 Flow enhanced new bone formation in the cortical drilled defects, whereas control defects showed very little newly formed bone.