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Fatigue has received little attention in the irritable bowel syndrome. Emerging evidence exists that leptin may be involved in the pathogenesis of fatigue in several conditions. We aimed to evaluate the occurrence of fatigue and its characteristics in irritable bowel syndrome and to analyze the relationship between fatigue and leptin.We enrolled 51 consecutive irritable bowel syndrome patients and 22 healthy controls without fatigue. None of them were depressed. The Fatigue Impact Scale was used to evaluate fatigue.In all, 62.7% of irritable bowel syndrome patients verbally expressed fatigue and rated more than 4 on the visual analog scale. The total score of fatigue was significantly higher in irritable bowel syndrome than in controls. In irritable bowel syndrome patients, but not in controls, a significant association was found between the total score of fatigue and leptin and this association was more pronounced in 32 irritable bowel syndrome patients who verbally expressed fatigue (r=0.60; P=0.0003). In irritable bowel syndrome, leptin correlated with fatigue independently from age, sex, fat mass and body mass index.Our study shows that fatigue occurs in 62.7% of irritable bowel syndrome patients when systematically asked for. Fatigue influences all three domains of the Fatigue Impact Scale in irritable bowel syndrome, the most being the physical and the psychosocial domains. Fatigue is associated with circulating leptin levels independently from age, sex, fat mass and body mass index in irritable bowel syndrome. The metabolic sequence involved in the occurrence of fatigue remains to be determined.