Traumatic brain injury (TBI), like other central nervous system pathologies, causes changes in the composition of cerebrospinal fluid (CSF). Consequently analysis of the CSF components is important to better understand the pathological processes involved in such diseases. The aim of this work was to identify specific markers of severe TBI. Proteomic analysis including two-dimensional gel electrophoresis combined with mass spectrometry analysis was used to compare the CSF protein profile of severe TBI patients and controls. Proteins (α 1 antitrypsin, haptoglobin 1 α1, α2, and β) belonging to the acute phase response showed an increased expression in severe TBI patients. Two other proteins, identified as proteolytic degradation products of the carboxyl-terminal portion of the fibrinogen β, were present only in TBI patients. The presence of these markers could correlate with a post-traumatic local increase in fibrinolysis as well as to an inflammatory event following CNS tissue injury.