Objective The objective of this study was to investigate fatigue and cognitive impairments in systemic lupus erythematous (SLE) in relation to diffuse white matter microstructural brain damage. Methods Diffusion tensor MRI, used to generate biomarkers of brain white matter microstructural integrity, was obtained in patients with SLE and age-matched controls. Fatigue and cognitive function were assessed and related to SLE activity, clinical data and plasma biomarkers of inflammation and endothelial dysfunction. Results Fifty-one patients with SLE (mean age 48.814.3 years) were included. Mean diffusivity (MD) was significantly higher in all white matter fibre tracts in SLE patients versus age-matched healthy controls (p<0.0001). Fatigue in SLE was higher than a normal reference range (p<0.0001) and associated with lower MD (ss=-0.61, p=0.02), depression (ss=0.17, p=0.001), anxiety (ss=0.13, p=0.006) and higher body mass index (ss=0.10, p=0.004) in adjusted analyses. Poorer cognitive function was associated with longer SLE disease duration (p=0.003) and higher MD (p=0.03) and, in adjusted analysis, higher levels of IL-6 (ss=-0.15, p=0.02) but not with MD. Meta-analysis (10 studies, n=261, including the present study) confirmed that patients with SLE have higher MD than controls. Conclusion Patients with SLE have more microstructural brain white matter damage for age than the general population, but this does not explain increased fatigue or lower cognition in SLE. The association between raised IL-6 and worse current cognitive function in SLE should be explored in larger datasets.