Physical signs of corpus callosum (CC) dysfunction in some ALS patients have been reported in the form of mirror movements, which reflect a disruption in communication between motor hemispheres while an individual performs motor tasks (1). These studies suggest that sub-clinical levels of this damage may occur as an early manifestation of the disease, warranting further in vivo study of the CC in these patients. This proposition, as well as knowledge of its involvement in landmark histologic studies (2,3), has prompted the study of the CC with diffusion tensor imaging. While diffusion tensor imaging (DTI) results show that there are consistent abnormal microstructural changes manifesting in the CC in ALS (4–6), few studies have examined macro-structural differences of this region. One identified reduced gross size of the CC compared to controls (7), while another found evidence for increased white matter density (8). Given these discrepant results, the aim of this study was to examine size differences in geometrically-defined sub-regions of the CC in the native space of brain magnetic resonance images of patients with ALS compared to healthy controls. A difference in CC size observed in either direction would add another dimension to the current understanding of the micro-structural changes observed in studies cited above. For instance, a confirmed increase in CC area in ALS patients might indicate an underlying proliferative process such as reactive astrocytosis in response to neuronal death, whereas a smaller CC area in patients could instead imply isolated atrophy of neurons. A confirmation of CC macro-structural change could warrant additional study of the CC of individuals at various stages of the disease in order to illuminate the role of this structure in the natural history of motor neuron degeneration.