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Chronic pain and fatigue are common physical complaints among children and adolescents. Both symptoms can interfere considerably with daily life by affecting sleep and eating habits, engagement in physical and social activities, and school participation. The aim of this study was to examine the potential mediational role of fatigue in the relationship between pain and children's school functioning and overall health-related quality of life (HRQOL).Children seeking outpatient pain management services at two urban children's hospitals were recruited for this study. The combined sample includes 80 children and adolescents between the ages of 8 and 18 years (M=13.89, SD=2.57), 72.5% female, and their caregivers. The Pediatric Quality of Life Inventory (PedsQL 4.0) was used to assess HRQOL and the related PedsQL Multidimensional Fatigue Scale provided a comprehensive measure of fatigue.On the basis of Preacher and Hayes' mediation model (2004), fatigue functioned as a mediator between pain and overall HRQOL on the basis of both self and caregiver proxy reports. Fatigue functioned as a mediator between pain and school functioning on the basis of the caregiver proxy report only. Additionally, moderate relationships were found between self and caregiver proxy reports of HRQOL and fatigue, although children self-reported less fatigue, better school functioning, and greater quality of life than did their caregivers.Findings demonstrated that fatigue is a significant problem for many youth with chronic pain and may be an important target for clinical intervention.