Abstract Three patients with severe traumatic brain injury demonstrated significant improvement in arousal and initiation after administration of tricyclic antidepressants. The first patient showed improved motor and speech initiation in response to amitriptyline following several months of functional plateau. The second patient was minimally responsive 2 months after injury and demonstrated improved arousal following the use of desipramine. Both patients deteriorated when the medications were discontinued and improved again when they were restarted. These two cases provide strong evidence for a medication effect. The third patient began to verbalize following desipramine administration, despite being mute for more than a year after injury. Previous case reports describe cognitive-enhancing effects, such as improved arousal, attention, memory, and initiation, of dopaminergic agents, and in the caes of tricyclic antidepressants, effects on agitation. The role of norepinephrine in promoting neurological recovery after brain lesions has been demonstrated in animals. The cases presented here provide some of the first data to show similar efficacy in humans and underscore the need for controlled trials to better determine which patients will benefits.