INTRODUCTION: Critical sized bone defects above critical size do not heal completely by themselves and thus represent major clinical challenge to reconstructive surgery. Numerous bone substitutes have already been used to promote bone regeneration. Incorporation of bone grafts such as biphasic calcium phosphate (BCP) as osteoconductive materials has been proven to be effective in promoting bone healing in oral surgery. As it is considered a potential candidate for bone regenerating biomolecules which can help in rapid bone repair because of its composition, the biocompatible material "mineral trioxide aggregate"(MTA) is suggested to be promising. OBJECTIVES: To compare the efficacy of MTA on the process of bone healing alone and the combination of MTA with biphasic calcium phosphate MATERIALS AND METHODS: Sixteen rabbits will be divided into two experimental groups: (1) MTA, (2) MTA+BCP. Right and left critical size bone defects will be performed in the edentulous area of rabbit mandibles (diastema). Right side bone defects will be filled with MTA, while the left side bone defects will be filled with MTA in combination with BCP. The effect of both MTA and BCP on defect healing will be assessed histologically, histomorphometrically and immunohistochemically after 6 weeks postoperatively. RESULTS: Greater amount of new bone formation was noticed in the CSDs loaded with MTA and BCP. The amount of new bone formed was significantly higher in the MTA+BCP group when compared with the MTA group. Also bone cells activities appeared greater in the former group. CONCLUSIONS: MTA induces new bone formation via an osteoinductive action and can be added to bone grafts to enhance bone regenerative capacity