Pediatric craniofacial surgery is complicated by a shortage of autologous bone. Children between 2 and 10 years of age are especially problematic, as the dura has lost its potential to spontaneously heal large calvarial defects by approximately 2 years of age, and split calvarial grafts are often unavailable because of the underdeveloped diploic space until later childhood. We demonstrate the efficacy of a BMP-2-based system in repairing large-scale cranial defects in a rabbit model. Calvarial defects, 15 mm, were created in 18 adult New Zealand white rabbits, treated as follows: group 1, no repair (n = 6); group 2, absorbable collagen sponge (ACS) (n = 4); and group 3, recombinant human bone morphogenetic protein 2 delivered on ACS (rhBMP-2/ACS) (n = 8). Bone regeneration 6 weeks postoperatively was evaluated by 2- and 3-dimensional standard computed tomography, micro-computed tomography. Analysis of variance was performed using SPSS. The generated bone was also evaluated histologically. After 6 weeks, group 1 defects were on average 32.8% (SD, 8.8%) ossified. Group 2 defects were on average 34.4% (SD, 17.1%) ossified. Defects in group 3 were on average 96.9% (SD, 3.7%) ossified, significantly (P < 0.005) more than the defects in groups 1 and 2. rhBMP-2-induced bone was histologically and radiographically consistent with native bone. This study demonstrates the efficacy of rhBMP-2/ACS for the repair of calvarial defects in the rabbit model. rhBMP-2/ACS may offer a viable treatment option for craniofacial surgeons facing a shortage of bone, with the potential to replace autologous bone grafts and render their attendant morbidities obsolete.