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Introduction: Gulf War Illness is a type of chronic multisymptom illness, that affects about 30% of veterans deployed to the 1990-91 Persian Gulf War. Veterans deployed to Iraq/Afghanistan after 2000 are reported to have a similar prevalence of chronic multisymptom illness. More than 30 years after the Persian Gulf War, Gulf War Illness still has an unexplained symptom complex, unknown etiology and lacks definitive diagnostic criteria and effective treatments. Our recent studies have found that substantially smaller brainstem volumes and lower fiber integrity are associated with increased sleep difficulty and pain intensity in 1990-91 Persian Gulf War veterans. This study was conducted to investigate whether veterans deployed to Iraq/Afghanistan present similar brainstem damage, and whether such brainstem structural differences are associated with major symptoms as in Gulf War Illness. Methods: Here, we used structural magnetic resonance imaging and diffusion tensor imaging to measure the volumes of subcortices, brainstem subregions and white matter integrity of brainstem fiber tracts in 188 veterans including 98 Persian Gulf War veterans and 90 Iraq/Afghanistan veterans. Results: We found that compared to healthy controls, veterans of both campaigns presented with substantially smaller volumes in brainstem subregions, accompanied by greater periaqueductal gray matter volumes. We also found that all veterans had reduced integrity in the brainstem-spinal cord tracts and the brainstem-subcortical tracts. In veterans deployed during the 1990-91 Persian Gulf War, we found that brainstem structural deficits significantly correlated with increased sleep difficulties and pain intensities, but in veterans deployed to Iraq/Afghanistan, no such effect was observed. Discussion: These structural differences in the brainstem neurons and tracts may reflect autonomic dysregulation corresponding to the symptom constellation, which is characteristic of Gulf War Illness. Understanding these neuroimaging and neuropathological relationships in Gulf War and Iraq/Afghanistan veterans may improve clinical management and treatment strategies for modern war related chronic multisymptom illness. [ABSTRACT FROM AUTHOR]