Cognitive impairment is a frequent complication of multiple sclerosis (MS), generally reflecting subcortical dementia. In order to explore functional cortico-cortical connections in MS, we studied electroencephalogram (EEG) coherence in a group of 21 clinically defined MS patients. Patients also underwent magnetic resonance imaging (MRI) and neuropsychological examinations. Compared to unimpaired MS patients, cognitively involved patients had reduced short-distance and long-distance theta and alpha band coherencies. Anteroposterior and interhemispheric coherencies were significantly correlated with MRI lesion load immediately underlying cortex but not were exclusively associated with periventricular lesions. These data support the hypothesis that cognitive impairment in MS is mostly related to demyelination or axonal loss of cortico-cortical connections. In a second study, we evaluated the neurophysiological correlates of frontal lobe dysfunction. Frontal lobes are also involved in motor planning and execution. We evaluated the EEG movement-related potential (MRP) in MS patients with and without frontal neuropsychological deficits. Reaction times to the Stroop test, which evaluates frontal functions, and MRP components were delayed in both MS groups compared to normal subjects and in frontal compared to nonfrontal MS patients. These data suggest that frontal cognitive involvement in MS corresponds to abnormal bioelectrical activity also during simple motor tasks.