Magnetic resonance imaging studies using voxel-based morphometry (VBM) have been inconsistent in demonstrating volumetric differences in patients with restless legs syndrome (RLS). Since treatment, age and selection of patients may introduce a methodological bias, we conducted optimized VBM analyses in unmedicated elderly subjects reporting RLS. Two hundred-four voluntaries, 65.9 +/- 0.6 year-old, free of any significant medical condition and without previous neurological or psychiatric medication, participated at the study. After exclusion of subjects having sleep-related breathing disorders and previous silent infarct, 71 subjects, 54 without RLS (RLS-) and 17 having RLS (RLS+) were analyzed. No structural change in gray matter density was found in RLS+ subjects compared to RLS- subjects. Subjects with RLS+ symptoms showed a small gray matter volume in the left occipital region without, however, statistical significance. VBM analysis did not show any significant change in subcortical and cortical gray matter in unmedicated elderly subjects with RLS symptoms. These results confirm the lack of specificity of thalamic and subcortical changes in restless legs syndrome.