BACKGROUND Traditional reconstructive options for cranial defects include autogenous bone graft, bone substitutes, and synthetic materials. The established standard for repairing cranial defects is autogenous bone. However, young children do not have abundant donor sites for bone harvest, which leads to challenges in closing calvarial defects. Synthetic materials are not ideal alternatives because they require subsequent retrieval and are prone to infection. Their long-term effects on growth of the skull are also not well studied. Bone morphogenetic protein 2 (BMP-2), are shown to positively affect closure of cranial defects in animal models. We present a study comparing the efficacy and safety of closure of cranial defect with bone graft augmented with recombinant human BMP-2 (rhBMP-2) and compared with a series of patients treated with bone graft alone. METHODS This study is a retrospective multicenter evaluation of 36 patients spanning 5 years. Twenty-one patients undergoing cranial defect closure augmented with rhBMP-2 were compared with 15 patients who underwent cranial defect closure using cranial bone shavings alone. We measured preoperative and postoperative defect size on volumetric computed tomographic scan reconstructions to compare defect sizes. RESULTS The rhBMP-2 group had slightly increased proportional closure compared with the control group, 86% versus 76% (P < 0.018), respectively. Two patients in the rhBMP-2 group had postoperative fusion of a suture that was known to be patent at the time of cranial defect closure. No instances of brain edema, herniation, airway compromise, or other adverse effects directly attributable to rhBMP-2 were observed. CONCLUSIONS Bone morphogenetic protein 2 may increase the amplitude and uptake of cranial bone grafts in cranial defect closure. This study shows that defect sizes of up to 16 cm can be reliably closed using this technique. Postoperative fusion of uninvolved sutures in 2 patients indicates that rhBMP-2 may have unreported adverse effects; consideration of this finding should be weighed against the benefit of improved closure of calvarial defects.