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OBJECTIVE: To examine the independent effects of chronic regional and widespread pain syndromes on health and functional status after accounting for comorbid chronic fatigue using a co-twin control design. METHODS: We identified 95 twin pairs discordant for pain in which one twin had chronic regional or widespread pain and the other denied chronic pain. Demographic data, functional and psychological status, health behaviors, and symptoms based on the 1994 criteria for chronic fatigue syndrome (CFS) were assessed by questionnaire. Psychiatric diagnoses were based on structured interview. Random effects regression modeling estimated associations between chronic regional and widespread pain and each health measure with and without adjustment for CFS. RESULTS: Significant differences (p ≤ 0.05) were found within twin pairs discordant for chronic regional and widespread pain, for general health perception, and physical and mental health functioning as measured by summary scores from the Short Form-36. In addition, differences were observed within pain discordant pairs in psychological distress as measured by the General Health Questionnaire as well as the number of psychiatric diagnoses. Adjustment for CFS eliminated the association between chronic pain and mental health, but the association between chronic pain and poor general health, physical functioning, and sleep quality persisted (p ≤ 0.01). Only the intra-pair difference in physical functioning distinguished twins with regional vs widespread pain (p ≤ 0.05). CONCLUSION: Both chronic regional and widespread pain exact debilitating effects on perceived general health, physical functioning, and sleep quality independent of CFS. However, the psychological and psychiatric influence of chronic pain appears closely tied to CFS. Research should examine the additive role of CFS-like illnesses in patients with chronic pain, and its influence on treatment and outcome.