Although multiple sclerosis (MS) is an inflammatory demyelinating disease, there can be substantial axonal injury and loss. We therefore hypothesized that adaptive cortical changes may contribute to limiting functional impairment, particularly in the early stages of the disease. To test our hypothesis, we used functional magnetic resonance imaging (MRI) to characterize the localization and volumes of activation in the motor cortex during simple flexion-extension finger movements. There were differences in the patterns of cortical activation with movement between the 12 MS patients and the 12 normal controls. All patients showed greater relative supplementary motor area activation than did the normal controls. The relative hemispheric lateralization of sensorimotor cortex (SMC) activation decreased in direct proportion to the total cerebral T2-weighted MRI hyperintense lesion load. This appeared to be due primarily to increases in ipsilateral SMC activation with increasing lesion load in white matter of the hemisphere contralateral to the limb moved. The center of activation in the contralateral SMC was shifted a mean of 8.8 mm posterior in patients relative to controls, providing additional evidence for cortical adaptive responses to injury. The magnitude of this posterior shift in the SMC activation increased with greater T2 lesion loads. These observations demonstrate that cortical recruitment for simple finger movements can change both quantitatively and qualitatively in the SMCs of MS patients, suggesting that cortical reorganization or "unmasking" of latent pathways can contribute to functional recovery. These adaptive changes are another factor potentially limiting the strength of the relationship between MRI measures of pathology and clinical measures of disability.