The value of MRI findings for coma prognostication is a question of great clinical and pathological relevance. We describe MRI evidence of restricted diffusion in the splenium in 5 patients with coma after cardiopulmonary resuscitation following cardiac arrest. The most common clinical presentation of corpus callosum lesions (of any cause) is altered mental status, consistent with the global importance of these extensive inter-hemispheric fibers. In our four cases with bilateral splenium restricted diffusion, none of the patients recovered consciousness. One patient with a unilateral (likely embolic) restricted diffusion lesion had excellent recovery. In contrast to unilateral ischemic callosal lesions, we believe that generalized, midline splenium restricted diffusion occurring after cardiopulmonary arrest represents Wallerian degeneration of interhemispheric neurons rather than direct ischemic damage to the white matter or axons of the callosum and thus will likely portend a poor prognosis.