Background and objectivesRecently, in adults, the incidence and severity of fatigue was found to exist rather independently from the somatic diagnosis. Since fatigue is distressing when growing up with a chronic disease, we aim to investigate: (1) the prevalence and extent of fatigue among various paediatric chronic diseases and (2) the effect of fatigue on health-related quality of life (HRQoL).Design and settingCross-sectional study in two children’s hospitals.PatientsChildren and adolescents 2–18 years of age with cystic fibrosis, an autoimmune disease or postcancer treatment visiting the outpatient clinic.Outcome measuresFatigue and HRQoL were assessed using the Pediatric Quality of Life Inventory (PedsQL) multidimensional fatigue scale (with lower scores indicating more fatigue) and PedsQL generic core scales, respectively. Linear regression analysis and analysis of covariance were used to compare fatigue scores across disease groups and against two control groups. The effect of fatigue on HRQoL was calculated. Data were adjusted for age, sex and reporting method.Results481 children and adolescents were assessed (60% participation rate, mean age 10.7±4.9, 42% men). Children and adolescents with chronic disease reported more fatigue than the general population (mean difference −6.6, 95% CI −8.9 to –4.3 (range 0–100)), with a prevalence of severe fatigue of 21.2%. Fatigue scores did not differ significantly between disease groups on any fatigue domain. Fatigue was associated with lower HRQoL on all domains.ConclusionsFatigue in childhood chronic disease is a common symptom that presents across disease, age and sex groups. Fatigue affects HRQoL. Our findings underscore the need to systematically assess fatigue. Future studies should determine possible biological and psychosocial treatment targets.