The adult somatosensory system has shown reorganizational abilities at cortical and subcortical levels after peripheral nerve lesions. In the present study the effects of carpal tunnel syndrome (CTS) are investigated as reflected on the somatotopy of the primary cortical hand representation. Position and intensity of cortical sources activated by the separate electrical stimulation of median nerve and Digits 1, 3, and 5 of both affected and non-affected hands are evaluated by magnetoencephalographic (MEG) technique. Correlation of MEG results with patient-, physician- and neurophysiological-oriented evaluations of CTS was carried out. Patients showed changes in cortical hand somatotopy in strict relationship to self-referred assessment of symptoms and hand disability in daily activities, including: 1) a more extended representation of the affected hand when paresthesias prevailed; and 2) a more restricted representation due to lateral shift of the little finger was observed when pain symptoms dominated the clinical picture. Contralateral to the side of CTS, the cortical sources activated by Digit 5-stimulation appeared significantly enhanced with respect to contralateral ones from non-affected hand. When comparing the amplitude of peripheral sensory nerve action potentials of median and ulnar nerves to that of cortical responses (i.e., ECD strengths of M20 and M30 components after stimulation of Digits 3 and 5), a significant selective amplification of M30 with respect to M20 and sensory nerve action potential (SNAP) appeared during Digit 3 stimulation compared to that observed for Digit 5. This has been interpreted as a central magnification mechanism in brain responsiveness, possibly revealing a safety factor enabling sensory perception despite the small peripheral signal due to nerve trunk dysfunction. Hum. Brain Mapping 17:28–36, 2002. © 2002 Wiley-Liss, Inc.