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A frequent manifestation of multiple sclerosis (MS) is chronic fatigue syndrome, which can be defined as a subjective decrease in the level of physical and/or mental energy. Chronic fatigue syndrome can be divided into asthenia (fatigue at rest), pathological fatigability (fatigue on physical loading), and fatigue on the background of deterioration of other symptoms (exacerbation of MS). There are both central and peripheral mechanisms for the formation of fatigue. The combination of fatigue and affective disturbances, especially depression and sleep disorders (insomnia, restless legs syndrome) is common in MS and may provide evidence that they share common mechanisms — decreases in the activity of the serotoninergic and noradrenergic systems. An important component in the formation of chronic fatigue syndrome consists of endocrine and autoimmune factors, the latter having a greater effect on asthenia than on pathological fatigue. Further studies of the pathogenetic mechanisms of the formation of asthenia and pathological fatigue and clarification of their differential diagnostic signs should allow not only a better understanding of the nature of this syndrome, but also better selection of individual treatment.