Recent studies indicate that motor imagery is subserved by activation of motor information. However, at present it is not clear whether the sparing of motor efferent pathways is necessary to perform a motor imagery task. To clarify this issue, we required patients with a selective, severe de-efferentation (locked-in syndrome, LIS) to mentally manipulate hands and three-dimensional objects. Compared with normal controls, LIS patients showed a profound impairment on a modified version of the hand-laterality task and a normal performance on mental rotation of abstract items. Moreover, LIS patients did not present visuomotor compatibility effects between anatomical side of hands and spatial location of stimuli on the computer screen. Such findings confirmed that the motor system is involved in mental simulation of action but not in mental manipulation of visual images. To explain LIS patients' inability in manipulating hand representations, we suggested that the pontine lesion, both determined a complete de-efferentation, and affected a component of the motor system, which is crucial for mental representation of body parts, probably the neural connections between parietal lobes and cerebellum.