Closed head injury (CHI) remains the leading cause of death and persisting neurological impairment in young individuals in industrialized nations. Research efforts in the past years have brought evidence that the intracranial inflammatory response in the injured brain contributes to the neuropathological sequelae which are, in large part, responsible for the adverse outcome after head injury. The presence of hypoxia and hypotension in the early resuscitative period of brain-injured patients further aggravates the inflammatory response in the brain due to ischemia/reperfusion-mediated injuries. The profound endogenous neuroinflammatory response after CHI, which is phylogenetically aimed at defending the intrathecal compartment from invading pathogens and repairing lesioned brain tissue, contributes to the development of cerebral edema, breakdown of the blood-brain barrier, and ultimately to delayed neuronal cell death. However, aside from these deleterious effects, neuroinflammation has been recently shown to mediate neuroreparative mechanisms after brain injury as well. This "dual effect" of neuroinflammation was the focus of extensive experimental and clinical research in the past years and has lead to an expanded basic knowledge on the cellular and molecular mechanisms which regulate the intracranial inflammatory response after CHI. Thus, head injury has recently evolved as an inflammatory and immunological disease much more than a pure traumatological, neurological, or neurosurgical entity. The present review will summarize the so far known mechanisms of posttraumatic neuroinflammation after CHI, based on data from clinical and experimental studies, with a special focus on the role of pro-inflammatory cytokines, chemokines, and the complement system.