OBJECTIVE: To determine the association between brain white matter (WM) damage and persistent fatigue among patients with granulomatosis with polyangiitis (GPA). METHODS: A case-control MRI study was conducted. Both cases, defined as GPA patients with chronic fatigue, and controls, defined as GPA patients without fatigue, underwent MRI brain scanning. Standard T1, T2 and FLAIR images were acquired and Scheltens white matter hyperintensity scores (SWMHS) reported in order to quantify macroscopic damage. In addition, diffusion tensor imaging (DTI) data were analysed using track-based spatial statistics to measure structural integrity and thus microscopic damage. RESULTS: No statistically significant differences in macroscopic damage were observed between cases (n = 14) and controls (n = 14) (median SWMHS 6, interquartile range 3-7 vs median SWMHS 3.5, interquartile range 3-8; P = 0.52). Compared with controls, there were no regions of WM where cases recorded reduced structural integrity; however, significantly greater structural integrity was registered in the regions of the fornix and cingulum nerve bundles of cases (P < 0.05, corrected for multiple comparisons). CONCLUSION: This study found no evidence to suggest that GPA-related fatigue is associated with either macroscopic or microscopic damage of the WM. On the contrary, regions of significantly greater structural integrity were observed among fatigued cases, which may reflect sustained activation secondary to chronic fatigue exposure.