Corpus callosum (CC) atrophy by magnetic resonance imaging (MRI) is a common finding in multiple sclerosis (MS). In order to examine the relationship between CC atrophy and cortical brain metabolism, we compared the cerebral metabolic rates for glucose (CMRglc), measured by positron emission tomography (PET), of 8 MS patients with evidence of CC atrophy on midsagittal MRI, 8 MS patients without CC atrophy and 10 healthy controls. Results showed no significant differences in supratentorial CMRglc absolute values between the three groups, although a slight metabolic reduction was observed in both MS groups compared with normal controls. By contrast, only patients with CC atrophy showed greater directional metabolic asymmetry than normals, the left frontal, temporal and parietal association cortices being significantly lower than the right. Predominant left hemispheric metabolic reductions were not accompanied by a corresponding left-sided predominance in the extent of MRI-detected demyelinating lesions. Therefore our data suggest that CC atrophy interfers more with left than with right metabolic function.