Chronic fatigue syndrome (CFS) is characterized by unexplained, disabling fatigue and is associated with high rates of comorbid depression. While the aetiology is unknown, findings from recent twin surveys suggest that genetic factors may be relevant to prolonged fatigue states (> 1 month). To date, however, there has been no exploration of the role of familial/genetic factors in operationally defined CFS. The aims of the present study were: (i) to examine whether CFS is familial by comparing the rates of CFS in the first-degree relatives of CFS cases and medical control subjects; and (ii) to determine whether the high rate of comorbid depression in CFS is reflected in a greater familial loading for affective disorder. Twenty-five CFS cases and 36 medical control subjects were assessed for fatigue symptoms based on the Centre for Disease Control (CDC) criteria for CFS, and for lifetime psychiatric symptoms using the Schedule for Schizophrenia and Affective Disorders-Lifetime Version. Informant family history was obtained regarding first-degree relatives using the CDC criteria and the Family History Research Diagnostic Criteria. In addition, informant history was supplemented by sending a questionnaire to first-degree relatives. There were significantly higher rates of CFS in the relatives of CFS cases compared with the relatives of control subjects. The rate of depression in the CFS cases was similar to previous studies but did not appear to reflect a greater familial loading for depression when compared with control subjects. However, these analyses were complicated by higher than expected rates of depression in the control group. These findings suggest that familial factors are important in the aetiology of chronic fatigue syndrome.