Background: Particulate bone graft and recombinant human bone morphogenetic protein-2 (rhBMP-2) are options for inlay cranioplasty in children who have not developed a diploic space. The purpose of this study was to determine whether particulate bone graft or rhBMP-2 has superior efficacy for inlay cranioplasty and to compare these substances to split cranial bone. Methods: A 17 mm xx 17 mm critical-sized defect was made in the parietal bones of 22 rabbits and managed in four ways: Group I (no implant; n=5), Group II (particulate bone graft; n 5), Group III (rhBMP-2; n=7), and Group IV (split cranial bone graft; n=5). Animals underwent microcomputed tomography and histologic analysis 16 weeks after cranioplasty. Results: Defects without an implant (Group I) demonstrated inferior ossification (41.4%; interquartile range [ IQR], 28.9% to 42.5%) compared to those treated with particulate bone graft (Group II: 99.5%; IQR, 97.8% to 100%), rhBMP-2 (Group III: 99.6%; IQR, 99.5% to 100%), or split cranial bone (Group IV: 100%) (P < .0001). There was no difference between Groups II, III, and IV (P.1). Defects treated with rhBMP-2 exhibited thinner bone (0.90 mm; IQR, 0.64 to 0.98) than particulate bone graft (1.95 mm; IQR, 1.09 to 2.83) or split cranial bone (1.72 mm; IQR, 1.54 to 1.88) (P=.006); particulate and split cranial bone grafted defects had a similar thicknesses (P=.6). Conclusions: Particulate bone graft, rhBMP-2, and split cranial bone close inlay calvarial defect areas equally, although the thickness of bone healed with rhBMP-2 is inferior. Clinically, particulate bone graft or split cranial bone graft may be superior to rhBMP-2 for inlay cranioplasty.