Purpose The purpose of this study was to investigate the differences of gray matter volume (GMV) alteration patterns between hemodialysis with restless legs syndrome (HD-RLS) and hemodialysis without restless legs syndrome (HD-nRLS) patients using voxel-based morphometry. Methods Twenty-three HD-RLS patients, 27 HD-nRLS patients, and 27 age-, sex-, and education-matched healthy controls were included in this study. One-way analysis of covariance and post hoc analyses were used to assess differences in GMV, demographics, and clinical data among the 3 groups. Pearson correlation analysis was conducted between altered GMV in the HD-RLS group and clinical data. Results Compared with HD-nRLS patients, HD-RLS patients showed decreased GMV in the left primary motor cortex (false discovery rate corrected,P< 0.05). Compared with the healthy controls, both HD subgroups (ie, those with and without RLS) exhibited consistent GMV changes, including decreased GMV in the bilateral anterior cingulate and paracingulate gyrus and left middle temporal gyrus (false discovery rate corrected,P< 0.05). The GMV values in the left precentral gyrus were negatively correlated with the RLS rating scores (r= 0.2138,P= 0.0263). Conclusions This abnormal decreased GMV in the sensorimotor cortex provides evidence for a sensory processing disorder in RLS that may be involved in the pathogenesis of RLS in HD patients.