Traumatic brain injury (TBI) alters the lives of millions of people every year. Although mortality rates have improved, attributed to better pre-hospital care and reduction of secondary injury in the critical care setting, improvements in functional outcomes post-TBI have been difficult to achieve. Diffusion-tensor imaging (DTI) allows detailed measurement of microstructural damage in regional brain tissue post-TBI, thus improving our understanding of the extent and severity of TBI. Twenty subjects were recruited from a neurological intensive care unit and compared to 18 healthy control subjects. Magnetic resonance imaging (MRI) scanning was performed on a 3.0-Tesla Siemens TIM Trio Scanner (Siemens Medical Solutions, Erlangen, Germany) including T1- and T2-weighted sequences and DTI. Images were processed using DTIStudio software. SAS (SAS Institute Inc., Cary, NC) was used for statistical analysis of group differences in 14 brain regions (25 regions of interests [ROIs]). Seventeen TBI subjects completed scanning. TBI and control subjects did not differ in age or sex. All TBI subjects had visible lesions on structural MRI. TBI subjects had seven brain regions (nine ROIs) that showed significant group differences on DTI metrics (fractional anisotropy, radial diffusion, or mean diffusion) compared to noninjured subjects, including the corpus callosum (genu and splenium), superior longitudinal fasciculus, internal capsule, right retrolenticular internal capsule, posterior corona radiata, and thalamus. However, 16 ROIs showed relatively normal DTI measures. Quantitative DTI demonstrates multiple areas of microstructual injury in specific normal-appearing white matter brain regions. DTI may be useful for assessing the extent of brain injury in patients with early moderate to severe TBI.