The outcome after severe traumatic brain injury (TBI) is largely unfavorable, with approximately two thirds of patients suffering from severe disabilities or dying during the first 6 months. Existing predictive models displayed only limited utility for outcome prediction in individual patients. Time courses of heart-fatty acidic binding protein (H-FABP) and their association with outcome were investigated and compared with S100b. Forty-nine consecutive patients with severe TBI (sTBI; Head component of the Abbreviated Injury Scale [HAIS] >3) with mono and multiple trauma were enrolled in this study. Enzyme-linked immunosorbent assay measured blood concentrations of H-FABP and S100b at 6, 12, 24, and 48 h after TBI. Outcome measures were conscious state at 14 days (Glasgow Coma Scale), disability (Glasgow Outcome Scale Extended; GOSE), and mortality at 3 months. Univariate logistic regression analysis and receiver operating characteristic curves analysis were carried out. Maximal H-FABP and S100b concentrations were observed at 6 h after TBI (34.4±34.0 and 0.64±0.99 ng/mL, respectively). Patients with multi-trauma had significantly higher H-FABP concentrations at 24 and 48 h (22.6±25.6 and 12.4±18.2 ng/mL, respectively), compared to patients with mono trauma (6.9±5.1 and 3.7±4.2 ng/mL, respectively). In the first 48 h, H-FABP and S100b were inversely correlated with the GOSE at 3 months; H-FABP at 48 h predicted mortality with 75% sensitivity and 93% specificity. Early blood levels of H-FABP after sTBI have prognostic significance for survival and disability.