Marchiafava-Bignami disease (MBD) is a rare pathological condition affecting the corpus callosum (CC), characterized by progressive demyelination and necrosis. While usually found in patients with chronic alcoholism, it has rarely been characterized in non-alcoholics. We describe a trauma patient with an unknown mechanism of injury, who was found to have MBD after remaining comatose for a prolonged period of time. Magnetic resonance imaging (MRI) demonstrated restricted diffusion involving the genu, body, and splenium of the CC. The patient eventually awoke but was non-communicative and uncomprehending prior to discharge to a nursing facility. We reviewed the literature and report here the first case of MBD encountered in a trauma patient. In conclusion, MBD is an extremely rare condition in non-alcoholic patients, and the use of MRI is crucial for its identification.