Various synthetic bone substitutes are not suitable for reconstructing critical-size bone defects. This study tested whether a bioglass-β-tricalcium phosphate (β-TCP) monoblock is effective for repairing critical-size segmental bone defects if combined with a vascularized periosteal flap and bone morphogenetic protein (BMP)-2. A femoral osteotomy with a gap size of 20 mm was created and stabilized using a plate in 40 rabbits.The defect was left untreated (group A) or repaired using a monoblock (group B), a monoblock with a vascularized periosteal flap (group C), or a monoblock with a vascularized periosteal flap and BMP-2 (group D). Bone regeneration, vascularization and monoblock degradation were analyzed after four and eight weeks using x-ray, hematoxylin-eosin, CD34 immunohistochemical and Masson's trichrome staining observation and histometric evaluation. The radiographic grading score showed a time-dependent increase from weeks 4 to 8. At 8-week postoperative, the total new regenerated bone in groups C and D was 20.0 ± 0.3 and 55.5 ± 8.0 mm , respectively, which was significantly greater than in group B. Conversely, group D showed less residual monoblock than did group C. An increase in microvessel density was also observed in groups C and D compared with group B at 4 and 8 weeks postoperative, respectively. This study suggests that bioglass-β-TCP monoblock alone exhibits poor potential to repair a 20-mm femoral defect. However, supplementation with a vascularized periosteal flap and BMP-2 led to effective vascularization and reliable bone regeneration throughout the monoblock, with concordant material degradation in a timely manner. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 2148-2156, 2018.