Neuropathological and experimental animal studies indicate that traumatic brain injury (TBI) results in long-term, neurodegenerative changes. Structural image evaluation using normalization of atrophy (SIENA) offers an automated analysis of the subtle changes in percent brain volume change (%BVC) associated with TBI. In the present study, SIENA was used to evaluate %BVC in individuals who had sustained a mild to severe TBI. We obtained three-dimensional (3D) T1-weighted anatomical magnetic resonance imaging (MRI) scans approximately 79 days and again 409 days post-injury. TBI patients (n = 37) displayed significantly greater decline in %BVC (-1.43%) relative to a normal comparison group (+0.1%, n = 30). Greater %BVC was associated with longer duration of post-injury coma. These results confirm previous findings from cross-sectional studies and argue that the brain undergoes continued structural change for several months post-injury.