Post-stroke Complex Regional Pain Syndrome (CRPS) is characterized by swelling, pain and changes in the skin that appear on the affected wrist and hand. In this retrospective study, we analyzed the relationship between post-stroke CRPS and the location of stroke lesion. From all patients admitted to our hospital from 2009 to 2019, we recruited eighty patients affected by their first unilateral stroke who met the inclusion/exclusion criteria. Thirty-eight patients diagnosed with CRPS after stroke were assigned to the experimental group according to the “Budapest criteria” adopted by the International Association for the Study of Pain, and 42 patients without CRPS were included as controls. Regions of interest were manually drawn on T1-weighted magnetic resonance images, and data were normalized to a standard brain template. In the post-stroke CRPS group, the relationship between the location of brain lesion and pain severity was analyzed using Freedman-Lane multivariable regression adjusting for Medication Quantification Scale rating, which was the only parameter to show a statistically significant correlation with pain intensity. A threshold of P < 0.01 was considered statistically significant for all VLSM tests, corrected for multiple comparisons with 5,000 permutations. Analyses using voxel-wise subtraction and Liebermeister statistics indicated that the corticospinal tract (CST) was associated with the development of post-stroke CRPS. Statistically significant correlations were found between pain intensity and the CST and the adjacent lentiform nucleus. Our results suggest that the CST may be a relevant neural structure for development of post-stroke CRPS and the intensity of pain caused by the syndrome.