BACKGROUND Fatigue is the most troublesome symptom in relapsing remitting multiple sclerosis (RRMS). It starts early in the disease course, escalates with disease progression and impacts the patients` quality of life. The aim of this work was to estimate the frequency of fatigue and to evaluate the relationship between severity of fatigue, clinical data, level of disability and volumetric brain atrophy in RRMS. METHODS 43 RRMS patients with 40 age- and sex-matched normal volunteers were recruited. Demographic and clinical data were recorded. Each participant was assessed with the Expanded Disability Status Scale (EDSS), Fatigue Severity Scale (FSS), Brief Cognitive Assessment for Multiple Sclerosis (BICAMS) and a variety of brain volumetric measures. RESULTS 31 (72.1%) of RRMS patients were found to have fatigue. There were no significant differences in demographic data between patients with or without fatigue according to FSS. However, patients with fatigue had a higher number of attacks, and higher scores in the EDSS and BICAMS than non-fatigued patients. There was a greater reduction in total brain volume, cerebral grey matter, and brain stem, thalamic and caudate volumes in fatigued compared with the non-fatigued patients and controls. FSS was significantly correlated with patients' age, duration of illness, total number of attacks, EDSS, and BICAMS. Total brain, cerebral grey matter and thalamic volumes all had negative correlations with fatigue severity. Regression analysis showed that EDSS accounted for 46% of the variance in fatigue scores while thalamic and brainstem atrophy accounted for 50.7%. CONCLUSIONS Fatigue was fairly common in RRMS patients. Level of disability and atrophy of the thalamus and brain stem were the best predictors of fatigue.