Objectives: To identify structural connectivity change occurring during the first 6 months after traumatic brain injury and to evaluate the utility of diffusion tensor tractography for predicting long-term outcome. Methods:The participants were 28 patients with mild to severe traumatic axonal injury and 20 age-and sex-matched healthy control subjects. Neuroimaging was obtained 0-9 days postinjury for acute scans and 6-14 months postinjury for chronic scans. Long-term outcome was evaluated on the day of the chronic scan. Twenty-eight fiber regions of 9 major white matter structures were reconstructed, and reliable tractography measurements were determined and used. Results:Although most (23 of 28) patients had severe brain injury, their long-term outcome ranged from good recovery (16 patients) to moderately (5 patients) and severely disabled (7 patients). In concordance with the diverse outcome, the white matter change in patients was heterogeneous, ranging from improved structural connectivity, through no change, to deteriorated connectivity. At the group level, all 9 fiber tracts deteriorated significantly with 7 (corpus callosum, cingulum, angular bundle, cerebral peduncular fibers, uncinate fasciculus, and inferior longitudinal and fronto-occipital fasciculi) showing structural damage acutely and 2 (fornix body and left arcuate fasciculus) chronically. Importantly, the amount of change in tractography measurements correlated with patients' long-term outcome. Acute tractography measurements were able to predict patients' learning and memory performance; chronic measurements also determined performance on processing speed and executive function. Conclusions:Diffusion tensor tractography is a valuable tool for identifying structural connectivity changes occurring between the acute and chronic stages of traumatic brain injury and for predicting patients' long-term outcome. Neurology ® 2011;77:818-826 GLOSSARY AB ϭ angular bundle; AF ϭ arcuate fasciculus; CB ϭ cingulum bundle; CC ϭ corpus callosum; CCab ϭ anterior body of the corpus callosum; CCg ϭ genu of the corpus callosum; CCpb ϭ posterior body of the corpus callosum; CCs ϭ splenium of the corpus callosum; CPF ϭ cerebral peduncular fibers; CPpa ϭ cerebral peduncular fibers to the parietal lobes; CVLT-II ϭ California Verbal Learning Test-II; DCA ϭ discriminant correspondence analysis; DTI ϭ diffusion tensor imaging; FA ϭ fractional anisotropy; FB ϭ fornix body; FC ϭ fornix crus; GCS ϭ Glasgow Coma Scale; IFO ϭ inferior fronto-occipital fasciculus; ILF ϭ inferior longitudinal fasciculus; MD ϭ mean diffusivity; PLS ϭ partial least-squares; ROI ϭ region of interest; TAI ϭ traumatic axonal injury; TBI ϭ traumatic brain injury; UF ϭ uncinate fasciculus.Traumatic axonal injury (TAI) is strongly linked to high mortality and morbidity in traumatic brain injury (TBI).1 TAI is progressive with typical occurrence of cytoskeletal disruption within 4 -6 hours postinjury and disconnection of axons between 1 and 7 days.2 Secondary axotomy, which damages brain structur...