See Sastre et al. (doi:10.1093/brain/awy225) for a scientific commentary on this article. Traumatic brain injury (TBI) is a risk factor for subsequent neurodegenerative disease. Zanier et al. report that single severe TBI induces tau pathology in humans and mice. Studies in the latter provide evidence that this pathology is self-propagating and can be transmitted between animals, causing brain dysfunction like a prion. Abstract Traumatic brain injury is a risk factor for subsequent neurodegenerative disease, including chronic traumatic encephalopathy, a tauopathy mostly associated with repetitive concussion and blast, but not well recognized as a consequence of severe traumatic brain injury. Here we show that a single severe brain trauma is associated with the emergence of widespread hyperphosphorylated tau pathology in a proportion of humans surviving late after injury. In parallel experimental studies, in a model of severe traumatic brain injury in wild-type mice, we found progressive and widespread tau pathology, replicating the findings in humans. Brain homogenates from these mice, when inoculated into the hippocampus and overlying cerebral cortex of naïve mice, induced widespread tau pathology, synaptic loss, and persistent memory deficits. These data provide evidence that experimental brain trauma induces a self-propagating tau pathology, which can be transmitted between mice, and call for future studies aimed at investigating the potential transmissibility of trauma associated tau pathology in humans.