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Fatigue is a common disabling symptom of relapsing remitting multiple sclerosis (RRMS). Many studies have linked grey matter atrophy to fatigue, but white matter lesion load (WM-LL) has received less attention. Here we assess the relation between fatigue and regional WM-LL volumetric measures. 63 patients with RRMS participated in this study; mean age was 31.9 ± 8.1 years. Each patient provided demographic details and was scored on the expanded disability status scale (EDSS) and fatigue severity scale (FSS). VolBrain, a fully automated, operator-independent tool was used to assess WM-LL and whole brain volume. The patients were classified into three groups: no fatigue (FSS < 4), low to moderate fatigue (FSS ≥ 4 ≤ 5) and high fatigue (FSS > 5). 33.3% of patients had no significant fatigue, 25.4% had mild-to-moderate fatigue, and 41.3% had significant fatigue. Age, disease duration, relapses, and EDSS were positively correlated to fatigue severity (P = 0.034, 0.002, 0.009 and 0.001 respectively). Whole brain volume, total and regional WM-LL (juxtacortical, periventricular, infratentorial) were also correlated with fatigue severity. Ordinal regression analysis for fatigue severity showed EDSS and infratentorial lesion volume were the best predictors. In conclusion, EDSS and infratentorial lesion volume (cerebellar and brainstem) are the best predictors of fatigue severity. [ABSTRACT FROM AUTHOR]