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Patients with traumatic brain injury (TBI) are predisposed to heterotopic ossification, which is believed to be due to osteoinductive factors released at the site of the brain injury. To date, little is known about the presence of such factors in human cerebrospinal fluid (CSF). This study investigated whether CSF of TBI patients is osteoinductive. In addition, known osteoinductive factors--such as bone morphogenetic protein (BMP)-2, BMP-4, and BMP-7, and S100B--were measured in CSF. Eighty-four consecutive patients were classified according to brain pathology: TBI (n = 11), non-traumatic brain pathology (NTBP) (n = 26), and no brain pathology (control group) (n = 47). The osteoinductive effect of CSF was measured repeatedly in proliferation assays using a fetal human osteoblast cell line. The mean proliferation rate (normalized to the internal negative control) of the TBI, NTBP, and control groups was 138.2% (SD 13.1), 110.0% (SD 22.1), and 118.8% (SD 16.9), respectively. The potentially confounding effect of age was investigated further by restricting the selection of patients for analysis to that of the oldest patient in the TBI group and use of multiple regression analysis. After implementation of both, it was shown that age is highly unlikely to account for the higher rates of proliferation observed among the TBI patients in this study. Of note, the TBI group had a significantly higher mean proliferation rate than the NTBP (p = 0.001) and the control group (p = 0.006). S100B and BMP-2, -4, or -7 concentrations were measured using enzyme-linked immunosorbent assay (ELISA). There was no correlation between proliferation rates and S100B (r = 0.023). Only three of 36 CSF samples had measurable levels of BMP-2 and -7, and none had detectable concentrations of BMP-4. Consequently, it is unlikely that S100B or BMP-2, -4, or -7 are the putative osteoinductive factors. The results indicate that CSF from TBI patients has an osteoinductive effect in vitro. However, the osteoinductive factor has still to be characterized.