Bone induction with extracted and partially purified, naturally derived bone morphogenetic proteins (BMPs) has been demonstrated repeatedly in heterotopic and orthotopic sites of non-human primates. This spawned the investigation of bone regeneration in mandibular defects of human patients with naturally derived BMPs and was compared with osteogenesis in patients treated with autologous bone grafts (ABGs). The osteogenic device (OD) was formulated as a combination of human demineralized bone matrix as delivery system reconstituted with naturally derived BMPs. BMPs were extracted from bovine bone with chaotropic agents and purified by sequential chromatography. Thirteen patients with segmental mandibular defects were enrolled in the trial, 6 of whom received the OD and 7 the ABGs. Defects were reconstructed with a preformed titanium mesh. The OD was combined with sterile saline and applied to the defects as a paste. Autologous bone from the iliac crest was prepared as a cortico-cancellous bone graft and loaded into the titanium mesh. Patients were followed-up clinically and radiographically at 1 and 6 weeks, 3, 6, and 12-month post-implantation. A trephine biopsy of the implants was performed at 3 months post-implantation and the specimens examined on serial undecalcified sections. Histological examination showed that the OD induced bone in 2 of 6 patients treated. Histological examination of successful implanted OD exhibited mineralized bone trabeculae with copious osteoid seams lined by contiguous osteoblasts. Bone deposition directly onto non-vital matrix provided unequivocal evidence of osteoinduction. Of the 7 patients grafted with ABGs, 5 had histological evidence of osteogenesis. Morphometric analysis of the histological sections showed that, when successful, OD-treated defects had highly active osteogenesis compared with ABGs. Whilst this trial provides valuable insights for the use of BMPs in mandibular reconstruction further work is required to produce an OD that will perform reliably in clinical contexts.