T cell immunoglobulin and mucin domain-3 (Tim-3) may be implicated in neuroinflammation. Herein, we attempted to discern the role of serum soluble (s) Tim-3 as an inflammatory prognostic biomarker of severe traumatic brain injury (sTBI).In this prospective observational study of 112 sTBI patients and 112 controls, serum sTim-3 levels were determined, Rotterdam computed tomography (CT) classification and Glasgow coma scale (GCS) were selected as the two severity indicators, serum C-reactive protein (CRP) was regarded as an inflammatory biomarker, and poor prognosis was referred to as extended Glasgow outcome scale (GOSE) scores 1-4 at 180 days after trauma.Serum sTim-3 levels were markedly higher in patients than in controls (median, 4.2 ng/mL versus 0.7 ng/mL; P<0.001). Serum sTim-3 levels of patients were independently related to Rotterdam CT scores (β=1.126), GCS scores (β=-0.589), serum CRP levels (β=0.155) and GOSE scores (β=-0.211). Serum sTim-3 appeared as an independent predictor of post-traumatic 180-day mortality (odds ratio=1.289), overall survival (hazard ratio=1.208) and poor prognosis (odds ratio=1.293). Serum sTim-3 levels discriminated patients at risk of post-injury 180-day mortality and poor prognosis with areas under curve (AUCs) at 0.753 and 0.782, respectively. Serum sTim-3 levels combined with GCS scores and Rotterdam CT scores (AUC=0.869) exhibited significantly higher AUC than Rotterdam CT scores (P=0.026), but not than GCS scores (P=0.181) for death prediction and their combination (AUC=0.895) had significantly higher AUC than GCS scores (P=0.036) or Rotterdam CT scores (P=0.005) for outcome prediction.Elevated serum sTim-3 levels, in close correlation with traumatic severity and inflammation, are substantially associated with long-term death and poor outcome, indicating that serum sTim-3, as an inflammatory biomarker, may be of clinical significance in severity assessment and prediction of prognosis following sTBI.