Chronic fatigue syndrome (CFS) and the symptom of chronic fatigue may be accompanied by substantial functional disability. A volunteer sample of twins discordant for fatigue was identified from throughout the US. Fatigued twins were classified using three increasingly stringent definitions: (1) > or = 6 months of fatigue (119 pairs); (2) CFS-like illness based on self-report of the Centers for Disease Control and Prevention CFS research definition criteria (74 pairs); and (3) CFS assessed by clinical examination (22 pairs). Twins with chronic fatigue were compared with their unaffected co-twins on the eight standard scales and two physical and mental component summary scales from the medical outcomes study short-form health survey (SF-36). Substantial impairment was observed for fatigued twins across all levels of fatigue, while scores in the healthy twins were similar to US population values. Mean scores among fatigued twins on the physical and mental component summary scales were below 97 and 77%, respectively, of the US population scores. Diminished functional status was found across increasingly stringent classifications of fatigue and was associated with a dramatic decrement in physical functioning. The symptom of fatigue has a pronounced impact on functional status, especially in the domain of physical functioning.