Background: Many people with a traumatic brain injury (TBI), even mild to moderate, will develop major depression (MD). Recent studies of patients with MD suggest reduced fractional anisotropy (FA) in dorsolateral prefrontal cortex (DLPFC), temporal lobe tracts, midline, and capsule regions. Some of these pathways have also been found to have reduced FA in patients with TBI. It is unknown whether the pathways implicated in MD after TBI are similar to those with MD without TBI. This study sought to investigate whether there were specific pathways unique to TBI patients who develop MD. Methods: A sample of TBI-MD subjects (N = 14), TBI-no-MD subjects (N = 12), MD-no-TBI (N = 26), and control subjects (no TBI or MD, N = 23), using a strict measurement protocol underwent psychiatric assessments and diffusion tensor brain Magnetic Resonance Imaging (MRI). Results: The findings of this study indicate that (1) TBI patients who develop MD have reduced axial diffusivity in DLPFC, corpus callosum (CC), and nucleus accumbens white matter tracts compared to TBI patients who do not develop MD and (2) MD patients without a history of TBI have reduced FA along the CC. We also found that more severe MD relates to altered radial diffusivity. Conclusions: These findings suggest that compromise to specific white matter pathways, including both axonal and myelination aspects, after a mild TBI underlie the susceptibility of these patients developing MD. Hum Brain Mapp 35:227–237, 2014. © 2012 Wiley Periodicals, Inc.