The anaphylatoxin C5a is a potent mediator of inflammation in the CNS. We analyzed the intracerebral expression of the C5a receptor (C5aR) in a model of closed head injury (CHI) in mice. Up-regulation of C5aR mRNA and protein expression was observed mainly on neurons in sham-operated and head-injured wild-type mice at 24 h. In contrast, in TNF/lymphotoxin-alpha knockout mice, the intracerebral C5aR expression remained at low constitutive levels after sham operation, whereas it strongly increased in response to trauma between 24 and 72 h. Interestingly, by 7 days after CHI, the intrathecal C5aR expression was clearly attenuated in the knockout animals. These data show that the posttraumatic neuronal expression of the C5aR is, at least in part, regulated by TNF and lymphotoxin-alpha at 7 days after trauma.