Abstract Moderate to severe traumatic brain injury (TBI) should be considered as a chronic health condition. The corpus callosum is the brain region that suffers most from diffuse axonal injury, leading to long-term functional deficits. Few studies have considered the relationships between inter- and intrahemispheric functional connectivity and structural damages to the corpus callosum in chronic TBI patients. We examined how callosal functional connectivity and white matter alterations relate to clinical outcome using multimodal magnetic resonance imaging (MRI): structural MRI estimates callosal volume, diffusion-weighted MRI enables white matter integrity quantification, resting-state functional MRI assesses neural dysfunction. Seventy-four patients underwent a multimodal MRI session on average 5 years after a moderate-to-severe TBI. Multiple factorial analysis analyzed the relationships between clinical outcome (from severe disability to good recovery, assessed by the Glasgow Outcome Scale extended GOSE), callosal volume, diffusion metrics (fractional anisotropy and mean, axial, and radial diffusivity), and inter- and intrahemispheric functional connectivity. Multiple factorial analysis confirmed that patients with severe disability (GOSE 3-4) had more structural alterations in the corpus callosum than patients with a good recovery (GOSE 7-8). Most importantly, patients able to live independently but unable to work/study in a standard environment (GOSE 5-6) could not be described solely by structural features. They exhibited a lower interhemispheric connectivity between cortical regions mediated by the corpus callosum than patients with a good recovery, and a tendency towards a decrease in intrahemispheric connectivity compared with severely disabled patients. These findings suggest a complex long-term functional impact of moderate-to-severe TBI.