AIM Fatigue in children and adolescents with multiple sclerosis (caMS) is currently poorly understood. This review aimed to provide greater insight into this area and direction for future research by evaluating evidence of associations between fatigue and clinical, psychological, and social factors in caMS.METHOD Studies were identified by searching online databases, hand-searching reference lists, and requesting unpublished literature from key authors. Studies that examined fatigue in relation to at least one clinical, psychological, or social factor in caMS were included. Data on design, sample characteristics, measures of fatigue, clinical, psychological, and social variables, and key findings were extracted. Twelve studies were narratively synthesized.RESULTS Clinical factors appeared largely unrelated to fatigue, whereas associations between fatigue and tests of neurocognitive functioning, and fatigue and diagnosable psychiatric disorders, were mixed. However, fatigue and depressed mood consistently correlated. A small number of studies indicated associations between fatigue and reduced quality of life and school performance.INTERPRETATION A sufficient explanatory model of fatigue in caMS is lacking as studies in this area are few and diverse. Future research should endeavour to identify potentially modifiable clinical and psychosocial factors that are associated with fatigue in caMS so that interventions targeting such factors may be developed.Multiple sclerosis is a chronic neurodegenerative disorder characterized by inflammation and demyelination in the central nervous system, most often diagnosed in adulthood. 1 In rare cases, multiple sclerosis is diagnosed in childhood or adolescence.2 Paediatric acquired demyelinating syndromes, including paediatric multiple sclerosis, have an incidence rate of approximately 1 in 100 000. 3 In adult multiple sclerosis, sensory and motor impairments, optic neuritis, and bladder and bowel dysfunction are among the most common physical symptoms. In paediatrics, physical symptoms are less predominant but cognitive deficits more troublesome, typically affecting attention and processing speed, language, memory, and visuomotor functioning. [4][5][6] Moreover, psychosocial factors such as depression, lower quality of life, and fatigue are concerning features of paediatric multiple sclerosis, yet these features have received limited research attention to date. 6,7 Fatigue is the most common and one of the most disabling symptoms of multiple sclerosis, experienced by around 80% of adults with the disease. [8][9][10] Multiple sclerosis-related fatigue refers to a severe and overwhelming feeling of exhaustion and lack of energy, which may result in functional impairment.11 A growing body of evidence suggests that fatigue is also a significant problem in paediatric populations, affecting approximately 30% of the general adolescent population and a substantial proportion of children and adolescents with chronic illnesses such as cancer, rheumatoid arthritis, chronic pain, and neur...