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Fatigue is a common problem, which is found more frequently among women than men. To date, neither the etiology of fatigue nor the factors that explain the gender difference in its incidence are still fully understood.In a sample of men (n = 4,681) and women (n = 4,698) (age range, 15-64 years) in the Dutch National Survey of Morbidity and Interventions in General Practice, the gender differences in the underlying biological, psychological, and social factors of fatigue were analyzed.Both general and gender-specific factors were recognized. Men and women who experience complaints of fatigue appeared to be younger and more highly educated. They had more acute health complaints and more psychosocial problems and also showed a lower level of perceived health. Among women, only gender-specific biological complaints and psychosocial problems were related to fatigue. In addition, relevant sociodemographic variables included taking care of young children and being employed. Among men, fatigue was particularly related to having handicaps and severe chronic complaints. Taking care of young children did not make a difference in the male sample.Fatigue can only be adequately understood in a multicausal model with biomedical and psychosocial factors. Complaints of fatigue are too often ignored in general practice. By adopting a patient-centered style of communication, physicians can acquire a more complete picture of the patients' fatigue.