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Objective: Recent data indicate that ubiquitin is increased in serum after trauma and might regulate immune functions. Its cellular source is unknown. Because there have been no previous studies after traumatic brain injury (TBI), we determined whether ubiquitin immunoreactivity is increased in cerebrospinal fluid (CSF) after TBI., Design and Setting: Prospective observational study of patients, with a subsequent interventional study of animals., Subjects: The subjects were 14 patients with TBI, five patients with nontraumatic subarachnoid hemorrhage, ten nonneurologic controls, and seven cross-bred swine., Interventions: Standardized TBI., Measurements and Main Results: Ubiquitin immunoreactivity was analyzed by enzyme-linked immunosorbent assay and immunoblotting. Hemolysis was assessed spectrophotometrically. CSF ubiquitin levels (mean +/- sd) were 19 +/- 3 ng/mL in nonneurologic control patients, 81 +/- 48 ng/mL at 7 +/- 2 hrs after TBI (p = .002), and at the end of operation in patients with nontraumatic subarachnoid hemorrhage they were 104 +/- 68 ng/mL (p = .001). CSF and serum ubiquitin were measured for 7 days in six patients with TBI. In survivors (n = 3), CSF ubiquitin levels progressively recovered, whereas in nonsurvivors (n = 3), the levels increased until death. There was no difference in serum ubiquitin levels between survivors/nonsurvivors and there was no correlation between serum and CSF ubiquitin levels. In swine, CSF ubiquitin levels peaked at 8- to 30-fold higher than baseline at 60 min post-TBI and then declined with a half-life of 1.3 hrs. In CSF with hemolysis, peak ubiquitin levels were five-fold higher than without hemolysis (p < .05). Ubiquitin and hemoglobin correlations in CSF and after in vitro lysis of erythrocytes suggested that erythrolysis could account for no more than 23 +/- 16% of the CSF ubiquitin., Conclusions: CSF ubiquitin levels are increased more than four-fold in patients after TBI and nontraumatic subarachnoid hemorrhage. Peak CSF ubiquitin measurements in patients with TBI probably underestimated the actual peak, on the basis of data from the animal model. The progressive rise in CSF ubiquitin in patients with TBI who died suggests that lack of clearance could reflect lethal progression to irreversible brain damage. Erythrolysis is one potential source of CSF ubiquitin.