Functional alterations in noxious, sensory and motor circuits within the central nervous system may play an important role in the pathophysiology of complex regional pain syndrome (CRPS). The aim of the present study was to search for further evidence of hyperexcitability in the hemisphere contralateral to the affected limb in patients with CRPS by employing both psychophysical and transcranial magnetic stimulation (TMS) methods. Twelve patients with CRPS type I, confined to the distal part of a limb (six in an upper-limb and six in a lower-limb), were enrolled in the study. The quantitative thermal, mechanical and 'wind-up' like pain testing was performed at the most painful site in the affected limb and in the ipsilateral limb. Results were then compared to those found at mirror sites in the contralateral limbs. TMS was used to assess the inter-hemispheric difference in parameters of corticospinal excitability, intracortical inhibition, and intracortical facilitation. The quantitative thermal and mechanical testing showed significant differences in cold, heat and mechanical pain thresholds, as well as in the first and last 'wind-up' stimuli between the affected and the contralateral limbs of the CRPS patients. No significant differences between the ipsilateral unaffected limbs and their contralateral pair limbs were found. A significant reduction in the short intracortical inhibition associated with a significant increase of the I-wave facilitation was found in the hemisphere contralateral to the affected side in the upper-limb CRPS group. No significant inter-hemispheric asymmetry between the affected and the non-affected sides was revealed in the lower-limb CRPS group. Taken together, these results suggest that in patients with well-localized CRPS, there is evidence for sensory and motor CNS hyperexcitability, though it seems to involve only corresponding regions within the CNS rather than the entire hemisphere.