AB Background: Scientific evidence is mounting for an association between traumatic brain injury and enhanced osteogenesis. The aim of this study was to correlate the in vitro osteoinductive potential of serum with the features of fracture-healing and the extent of brain damage in patients with severe traumatic brain injury and bone fracture. Methods: Patients with a long-bone fracture and a traumatic brain injury (seventeen patients) or without a brain injury (twenty-four patients) were recruited. The Glasgow Coma Scale score was determined on admission. Radiographs of the fracture were made before surgery, at six weeks, and at three, six, and twelve months after surgery. The time to union was estimated clinically and radiographically, and the callus ratio to shaft diameter was calculated. Serum samples were collected at six, twenty-four, seventy-two, and 168 hours after injury, and their osteogenic potential was determined by measurement of the in vitro proliferation rate of the human fetal osteoblastic cell line hFOB1.19. Results: Patients with a traumatic brain injury had a twofold shorter time to union (p = 0.01), a 37% to 50% increased callus ratio (p <0.01), and their sera induced a higher proliferation rate in hFOB cells (p <0.05). A linear relationship was revealed between hFOB cell proliferation rates and the amount of callus formed (p <0.05). The Glasgow Coma Scale score was correlated with the callus ratio on both radiographic projections (p <0.05), time to union (p = 0.04), and the proliferation rate of hFOB cells at six hours after injury (p = 0.03). Conclusions: Patients with a severe brain injury release unknown humoral factors into the blood circulation that enhance and accelerate fracture-healing.