OBJECTIVE To determine if psychological morbidity in youth with chronic fatigue is caused by the stress of coping with a chronic illness. METHODS Case-control study comparing pediatric patients with debilitating chronic fatigue and matched subjects with juvenile rheumatoid arthritis, a chronic medical illness with similar functional sequelae. METHODS Pediatric Infectious Diseases Clinic and Juvenile Rheumatoid Arthritis Clinic of Kosair Children's Hospital. METHODS Nineteen children and adolescents with debilitating chronic fatigue and 19 age- and sex-matched peers with juvenile rheumatoid arthritis. Outcome. Structured Interview, Kaufman Brief Intelligence Test, Child Behavior Checklist, and Youth Self-Report. RESULTS Intellectual functioning on the Kaufman Brief Intelligence Test Composite was average (103, standard score) for both groups. Pediatric patients with chronic fatigue had higher levels of internalizing psychological distress than patients suffering from juvenile rheumatoid arthritis, despite the fact that both groups had a similar pattern of decline in social and physical activities. Duration of illness did not explain the difference in psychological symptoms. CONCLUSIONS Psychological factors may play a more active role in debilitating chronic fatigue in pediatric patients than can be explained by the stress of coping with a similar chronic, non-life-threatening illness.