Conventional clinical neuroimaging is insensitive to axonal injury in traumatic brain injury (TBI). Immunocytochemical staining reveals changes to axonal morphology within hours, suggesting potential for diffusion-weighted magnetic resonance (MR) in early diagnosis and management of TBI. Diffusion tensor imaging (DTI) characterizes the three-dimensional (3D) distribution of water diffusion, which is highly anisotropic in white matter fibers owing to axonal length. Recently, DTI has been used to investigate traumatic axonal injury (TAI), emphasizing regional analysis in more severe TBI. In the current study, we hypothesized that a global white matter (WM) analysis of DTI data would be sensitive to TAI across a spectrum of TBI severity and injury to scan interval. To investigate this, we compared WM-only histograms of a scalar, fractional anisotropy (FA), between 20 heterogeneous TBI patients recruited from Detroit Medical Center, including six mild TBI (GCS 13-15), and 14 healthy age-matched controls. FA histogram parameters were correlated with admission GCS and posttraumatic amnesia (PTA). In all cases, including mild TBI, patients' FA histograms were globally decreased compared with control histograms. The shape of the TBI histograms also differed from controls, being more peaked and skewed. The mean FA, kurtosis and skewness were highly correlated suggesting a common mechanism. FA histogram properties also correlated with injury severity indexed by GCS and PTA, with mean FA being the best predictor and duration of PTA (r = 0.64) being superior to GCS (r = 0.47). Therefore, in this heterogeneous sample, the FA mean accounted for 40% of the variance in PTA. Increased diffusion in the short axis dimension, likely reflecting dysmyelination and swelling of axons, accounted for most of the FA decrease. FA is globally deceased in WM, including mild TBI, possibly reflecting widespread involvement. FA changes appear to be correlated with injury severity suggesting a role in early diagnosis and prognosis of TBI.