ObjectiveTo evaluate bioactivity and osteogenic potential of calcium silicate (CS)-doped iron oxide (Fe2O3) nanoparticles versus pure CS in the reconstruction of induced critical-sized mandibular defects. DesignCS-doped Fe2O3 was prepared; morphological and microstructure identification of nanoparticles were made. An in vivo randomised design was developed on 24 adult male dogs where four critical-sized mandibular defects were created in each dog. Bone defects were allocated into control, CS, CS-3% Fe2O3 and CS-10% Fe2O3 group. Dogs were euthanized at 1 and 3 months (12 dog/time) for histopathologic and histomorphometric evaluation. ResultsAt three months, bone formation and maturation were evident where mean ± SD percent of mature bone was 2.66 ± 1.8, 9.9 ± 2.5, 22.9 ± 4.9, and 38.6 ± 8.1 in control, CS, CS-3% Fe2O3, and CS-10% Fe2O3 groups respectively. A high significant (P < 0.001) increase in area percent of mature bone was recorded in CS, CS-3% Fe2O3, and CS- 10% Fe2O3 groups compared to control group (73%, 88% and 93.3% respectively). Significant increase (P < 0.001) in area of mature bone was recorded in CS-3% Fe2O3 and CS-10% Fe2O3 groups compared to CS group. A significant increase (P < 0.001) in area of mature bone formation was detected in CS-10% Fe2O3 group compared to other groups. ConclusionCS-doped Fe2O3 has good osteoconductive, biocompatible properties with promoted bone regeneration. Fe2O3 has synergistic effect in combination with CS to promote bone formation. Increasing concentration of Fe2O3 nanoparticles resulted in improved osteogenesis and maturation. Results suggests that the novel CS-Fe2O3 alloplasts could be used for reconstruction of critical-sized bone defects.