Background: Hemodialysis (HD) causes various nervous system abnormalities. Alterations in white matter (WM) microstructure after long-term HD have been reported in a few previous studies; however, no studies have been performed to investigate enlarged perivascular spaces (PVS) in WM regions. We measured cerebral blood flow (CBF) and white matter volume (WMV) in HD patients to assess enlarged PVS severity in the WM across the whole brain and suggest possible explanations for this. Methods: Fifty-one HD patients and 51 age-, sex-, and education-matched healthy controls (HCs) were recruited. The number of enlarged PVS in the centrum semiovale (CS), cerebral watershed (CW), and basal ganglia (BG) regions were assessed by T2-weighted MRI. CBF was estimated by arterial spin labeling (ASL), which is a non-invasive perfusion imaging technique. WMV was assessed by the computational anatomy toolbox (CAT12), which is a statistical analysis package. Differences in descriptive variables (two-tailed t-tests, chi(2) tests, Mann-Whitney U tests, and Friedman M tests), an intra-class correlation between radiologists, the relationship between enlarged PVS number and HD duration, normalized CBF and WMV (multiple regression), and group differences in CBF and WMV {voxel-wise t-tests with age and sex as covariates [cluster size >50 voxels, false discovery rate (FDR) corrected, P<0.05]} were assessed. Results: HD patients displayed a more significant number of CS-PVS and CW-PVS in WM regions compared with the HCs, but there was no significant difference in the number of BG-PVS. The number of CS-PVS and CW-PVS were positively associated with HD duration. The number of CW-PVS was positively associated with CBF changes and WMV alteration in HD patients. Meanwhile, significant differences in the blood pressure (BP) readings pre-HD, intra-HD, and post-HD were observed in HD patients. Compared with the HCs, the HD patients showed higher CBF in the CS, CW, and BG regions (P<0.05). Hence, decreased WMV in the CS, CW, and BG regions were shown in the HD patients compared with the HCs (P<0.05). Conclusions: Enlarged CS-PVS and CW-PVS on MRI might be a feature of long-term HD patients. Enlarged CW-PVS number is associated with higher CBF in the CW region and lower WMV in the CW region in HD patients.