The alien hand sign. Localization, lateralization and recovery. The alien hand sign was first described by Brion and Jedynak as a "feeling of estrangement between the patient and one of his hands." The affected hand frequently shows a grasp reflex and an instinctive grasp reaction as well as elements of what Denny-Brown referred to as a "magnetic apraxia" associated with frontal lobe damage. Most notably, however, the affected hand is observed to perform apparently purposive behaviors that are perceived as being outside the volitional control of the patient. The patients interpret the behavior of their own affected limb as being controlled by an external agent. They do not feel that they are initiating or controlling the behavior of the hand and often express dismay at the hand's "extravolitional" activity. The patients attempt to control behavior of the alien hand with the unimpaired hand by forcibly restraining the affected limb, an act that may be termed "self-restriction." In this paper, we report an additional four cases of alien hand sign in right-handed subjects: two involving the right hand and two involving the left hand. In each case, the clinical findings were associated with extensive unilateral damage of the medial frontal cortex of the hemisphere contralateral to the affected hand. Furthermore, the alien movement gradually disappears over the course of 6-12 months after the stroke. These clinical case studies are presented and discussed in the context of the "dual premotoer systems hypothesis," an anatomicophysiological model that proposes that action is organized by two separate but interactive premotor brain systems corresponding to evolutionarily defined medial and lateral cortical moieties. It is hypothesized that the alien mode behavior results from unconstrained activity of the lateral premotor system in the damaged hemisphere. The residual volitional control in the limb occurs through the activity of the intact medial premotor system of the ipsilateral hemisphere. Recovery may occur through extension of these ipsilateral control mechanisms by compensatory changes in subcortical systems controlling hemispheric activation associated with adaptive behavior. This observation may be important in understanding mechanisms involved in motor recovery after stroke. 