Aim: Comparing bone regenerative capacity of Bulk MTA with Nano MTA, nanohydroxyapatite and injectable platelet rich fibrin (i-PRF) in a rat bony defect.Materials and methods: 100 male adult albino rats were anesthetized and a bone defect was created in the right tibiae. Rats were randomly divided into two groups according to dates of scarification 7-21 days, which were then subdivided into five subgroups ten animals in each based on the defect filled by: Nano MTA, Nano hydroxyapatite, i-PRF, BulkMTA and empty defect as control. All the right tibiae were dissected for histological analysis and histomorphometric measurements to assess bone regeneration. Bone area percentage were calculated. Results: New bone formation was observed in all sub-groups. On day 7, histological analysis revealed partially filled defects with woven bone trabeculae with variable trabecular pattern enclosing fibro-cellular tissue spaces containing blood capillaries and collagen fibers. On day 21, all experimental groups showed newly formed mature bone, including the presence of organized osteocytes and reversal lines indicating bone remodeling. Histomorphometric analysis revealed that statistically important differences between bone formations in all treated sub-groups comparing to the untreated control sub-group in both interval times. However, an increase in the bone area percentage was observed throughout experimental periods in all sub-groups without statistical difference.Conclusion: It could be concluded that Nano MTA induced the most favorable tissue response and osteopromotion properties followed by Nano HA and i-PRF compared with conventional MTA. Although the results are very encouraging, more studies on i-PRF properties are mandatory before routine clinical use.