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Our study was carried out to determine the prevalence of chronic fatigue syndrome (CFS) within a selected population of patients suffering from persistent fatigue. We studied subjects with recurrent or persistent fatigue lasting 6 months and fulfilling at least four minor Center for Disease Control (CDC) criteria for the diagnosis of CFS. Evaluation included both clinical examination and laboratory testing. All subjects filled out a questionnaire specifically designed to gain information about the length and severity of symptoms, and patients with a previously diagnosed illness associated with fatigue were excluded. The study was carried out at the Fatigue Clinic of an internal medicine unit (Clinica Medica I) of the University of Rome "La Sapienza". Sixty-three subjects, residents of the Lazio region (central Italy), completed the diagnostic assessment. Alternative diagnoses were established in 37 (59%) of the 63 patients. A diagnosis of CFS based on the CDC criteria was established in only 6 cases. In 2 subjects, CFS had appeared following infectious mononucleosis, and no definitive diagnosis could be formulated for 18 patients. In Italy, CFS seems to be an infrequent cause of severe and persistent fatigue in a selected population. Numerous morbid conditions may be responsible for a clinical picture closely resembling CFS. We recommend that patients suffering from fatigue be thoroughly evaluated.