Many potential brain trauma biomarkers have been reported, but no previous study has described outcome prediction using combinations of biomarker levels. We aimed to investigate the outcome predictive values of multiple biomarkers from different mediator families and to determine whether combinations of two serum biomarkers may achieve higher outcome predictive values than individual biomarker levels. A prospective observational study was conducted involving 28 children requiring intensive care management following brain trauma. Day 1 post-injury serum concentrations of eight different biomarkers-S100b protein (S100b), neuron-specific enolase (NSE), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10 (IL-10), soluble intracellular adhesion molecule (SICAM), L-selectin, and endothelin-were quantified using enzyme-linked immunosorbent assay (ELISA). Global outcome was assessed at 6 months post-injury using the Glasgow Outcome Score (GOS). Receiver operator characteristic curve (ROC) analysis and its multivariate extension, Multivariate ROC (MultiROC), were used to assess the outcome predictive values of the individual and the paired biomarkers. None of the eight biomarkers assessed individually achieved an area under the ROC curve (AUC) of more than 0.95 for predicting unfavorable outcome, but five of the 20 biomarker pairs assessed had this high degree of outcome predictability. Two combinations using S100b as the "screening marker'' and either L-selectin or IL-6 as the "varying marker'' achieved an AUC of 0.98, and their specificity and sensitivity for unfavorable outcome prediction were 96% and 100%, respectively. Prognostic pairs combining serum levels of two biomarkers (inflammatory mediators and brain-specific proteins) offer better outcome predictive values for unfavorable outcome after childhood brain trauma than may be achieved using individual marker levels.