Key PointsQuestionAre levels of serum brain-derived tau (BD-tau) at admission associated with clinical outcome and long-term change in patients with severe traumatic brain injury (sTBI)?FindingsIn this cohort study of 39 patients with sTBI, the mean fold difference in serum BD-tau concentrations on day 0 for patients with sTBI with unfavorable clinical outcomes vs those with favorable clinical outcomes 1 year after the injury was higher than the mean fold differences in serum total tau and phosphorylated tau231. Serum BD-tau demonstrated slower clearance from the blood (56.6% of baseline levels remaining by day 7) compared with total tau and phosphorylated tau231, which had only 19.0% and 7.5% of baseline levels, respectively, remaining at day 7.MeaningThis study suggests that concentrations and longitudinal trajectories of serum BD-tau differ among patients with sTBI depending on clinical outcome; serum BD-tau could be used as an accessible biomarker to monitor clinical outcome in patients with sTBI at admission and 7 days after the injury.