Rationale: A subset of Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) Veterans who incur a mild traumatic brain injury (mTBI) experience persisting post- concussive symptoms (PCS) and objective cognitive deficits (e.g., slowed processing speed). However, these symptoms are not unique to mTBI; overlapping symptoms and similar cognitive deficits are also observed in post-traumatic stress disorder (PTSD), depression, and after deployment and blast exposure not resulting in mTBI, all of which are common for OEF/OIFVeterans. Although advanced neuroimaging techniques have improved our understanding of white matter changes after mTBI, measuring myelin integrity has the potential to be a sensitive and specific measure of slowed processing speed and PCS related to mTBI, and to help disentangle these symptoms from conditions with overlapping features. Design: Utilizing a novel neuroimaging method, multicomponent-driven equilibrium single-pulse observation of T1 and T2 (mcDESPOT), the present study aimed to assess the relationship between myelin integrity and 1) injury variables (i.e., number of TBIs, loss of consciousness and post-traumatic amnesia, blast-related TBI), 2) cognitive variables including objective tests of working memory/attention that require speeded processing and simple measures of processing and motor speed (n = 4), and 3) subjective PCS in OEF/OIF combat Veterans with and without TBI history. This cross-sectional study assessed 57 OEF/OIF Veterans with history of mTBI (n = 31), history of moderate TBI (n = 4), or without history of TBI (n = 22). Across the entire sample, the prevalence of PTSD was 52.6%. Groups did not significantly differ with regard to presence/severity of current PTSD or depression, self-reported alcohol use (current substance use disorder was exclusionary), or demographic variables. Myelin integrity was measured using mcDESPOT’s myelin water fraction (MWF) across multiple regions-of-interest (ROIs) in fronto-striatal and fronto-limbic circuits, and callosal fibers. Veterans were administered a comprehensive battery of neuropsychological tests including measures of simple and complex processing speed as well as PCS. Using partial correlations and multiple linear regression, relationships between myelin integrity and 1) injury variables, 2) cognition, and 3) subjective persistent PCS in the context of PTSD and depression were assessed. Results: There were no differences between the combat comparison (CC), mTBI, or moderate TBI (modTBI) groups with respect to myelin integrity or cognitive performance. However, PTSD was significantly and positively associated with MWF. Injury variables demonstrated inconsistent relationships with myelin integrity, such that number of TBIs and blast-related mTBI were positively associated with MWF, although the majority of these relationships did not survive Bonferroni correction and/or remain significant once controlling for PTSD. Significant and positive relationships were observed between MWF and objective cognitive measures (most notably a measure of speeded attention and processing) across multiple ROIs, when controlling for psychiatric diagnoses and/or symptoms. Furthermore, the relationship between MWF and cognition was significant within the mTBI, but not the CC group. Finally, no significant relationships were observed between MWF and PCS after controlling for psychiatric symptoms and/or diagnoses. Conclusions: Given the prevalence of TBI and psychiatric comorbidities in OEF/OIF Veterans, the identification of reliable and objective biomarkers of brain damage after mTBI would provide the foundation for more accurate diagnosis of nonspecific symptoms, prognosis, and therapeutic opportunities. Results suggest that assessing myelin integrity using mcDESPOT may be a useful tool in delineating nonspecific reports of cognitive difficulties occurring after TBI in the context of commonly comorbid psychiatric disorders.