Background: Traumatic brain injury (TBI) is a worldwide cause of morbidity and mortality. Pentraxin 3 (PTX3) is a humoral component of the innate immune system which has been studied as a marker of inflammatory, infections or cardiovascular pathologies. To investigate the association between serum levels of PTX3 and the hospital mortality of patients with severe TBI. Methods: The independent association between serum PTX3 levels after severe TBI (Glasgow Coma Scale, GCS ≤ 8) and hospital mortality was analyzed in a prospective study of 83 consecutive patients by a multiple logistic regression analysis. The leukocyte count in the same sample was analyzed as another marker of inflammatory response. Results: The mean age of patients was 35 years and 85% were male. Serum PTX3 levels were determined 18.0 (SD ± 17.0) h after TBI. Patients who died showed a mean serum PTX3 level of 9.95 μg/ml (SD ± 6.42) in comparison to 5.46 μg/ml (SD ± 4.87) of the survivor group ( P = 0.007). Elevated serum PTX3 levels remain significantly associated with mortality ( P = 0.04) in the subset of patients with isolated TBI ( n = 34). There were no differences in the leukocytes count measured in the same blood sample used for PTX3 determination in survivors and non-survivors ( P = 0.56). The final multiple logistic regression model including age, pupillary examination, GCS, associated trauma, and PTX3 levels shows that serum levels of PTX3 which were higher than 10 μg/ml were independently associated with the patients mortality (adjusted OR 3.06, CI 95% 1.03-9.15, P = 0.04). Conclusions: Serum PTX3 levels after severe TBI are independently associated with higher hospital mortality and may be a useful marker of TBI and its prognosis. [ABSTRACT FROM AUTHOR]