Background: Bone defects in oral and maxillofacial surgery may cause by neoplasms, cysts, trauma, and infection. The present study add knowledge to the existing literature about the effect of a mixture of platelet rich fibrin (PRF) and hydroxyapatite (HA) in the treatment of large periapical lesion. Materials &Method: Regenerative therapies including PRF and HA were used to obtain optimal healing of periapical bone defect following the excision of the lesion. Platelet rich fibrin contains and releases (through degranulation) at least seven different growth factors (cytokines) that stimulate bone and soft tissue healing. An easy, cost-effective way to obtain high concentrations of growth factors for tissue healing and regeneration is autologous platelet storage via PRF. Results: The combination of both PRF with hydroxyapatite (HA) in treatment of bone defect leads to better results, because PRF releases growth factors (cytokines) that stimulate bone and soft tissue formation. Conclusion: Accordingly, the use of PRF in conjunction with HA bone graft might have accelerated the resorption of the graft material and would have induced the rapid rate of bone formation.