A recent study described for the first time a patient group that suffered from spontaneous chronic pain and from recurrent herpes simplex virus (HSV) infections. The patients had pain in widespread areas on one side of the body and were--due to subtle immunological abnormalities--susceptible to HSV infections. Although the clinical features of the pain suggested involvement of the central nervous system, supporting evidence for this was lacking. The objective of this study was to search for changes in the central nervous system that could account for the chronic pain in these patients. We monitored the central processing of pain and touch in eight patients and 11 healthy control subjects, who received painful heat and innocuous tactile stimuli to the hands during functional magnetic resonance imaging. Possible changes in the gray matter density of the brain were assessed with voxel-based morphometry. We found functional changes in the patients' central pain circuitry: activation to heat pain was weaker than in control subjects in the insular cortices, anterior cingulate cortex (ACC), and thalamus, while the activations to innocuous tactile stimuli were similar in both groups. Gray matter density was decreased in the patients' frontal and prefrontal cortices and in the ACC. The observed functional and structural changes in the central pain circuitry, together with the clinical features of the chronic pain support the hypothesis for central involvement in the development of chronic pain in these patients.