Recent studies have reported a significant inflammatory reaction in the brain and the systemic circulation after traumatic brain injury (TBI). Although there is growing knowledge and understanding of the mechanisms and mediators involved in the proinflammatory reaction, little is known about the anti-inflammatory mediators in the brain. As tumor necrosis factor α (TNF-α) plays a detrimental role in the initiation and promotion of the proinflammatory reactions after TBI, the endogenous scavenger system, represented by the soluble TNF receptors (sTNFRs) p55 and p75, seems to have an important anti-inflammatory capacity by binding to circulating TNF-α. To evaluate this potentially anti-inflammatory response to trauma, we analyzed sTNFR p55 and p75 in paired plasma/cerebrospinal fluid (CSF) samples of 29 patients who encountered TBI. Values were compared with reference values obtained from healthy volunteers (n = 91). Patients with TBI showed significantly (P < 0.001) elevated sTNFR p55 and p75 values starting from day 2 and lasting until day 10 if compared with reference values. In contrast to the early increased plasma values p55 and p75 showed slowly increasing CSF values starting on day 4 and 3, respectively. Significantly (P < 0.001) increased CSF values of p 55 were determined on days 4 to 6 and day 9. p75 showed significantly (P < 0.001) elevated values if compared with control values on days 7 and 9. The sTNFR p55 and p75 show a distinct and long-lasting elevation in plasma of patients after TBI. In contrast, CSF values display a delayed and less intense elevation of both receptors in patients with TBI. These findings are suggestive of an imbalance of the proinflammatory and anti-inflammatory reactions of the central nervous system after trauma, with an emphasis on the proinflammatory mechanisms and a slow increase of potentially anti-inflammatory mediators such as the soluble TNFRs after TBI.