A high prevalence of mood disorders has been found among persons with chronic fatigue. The comorbidity of mood disorders and substance use disorders has long been recognized. In this study, the prevalence of substance use disorders among 100 patients with chronic fatigue was examined. Twenty-eight patients met DSM-III-R criteria for a lifetime diagnosis of substance abuse or dependence; ten of these patients had a current diagnosis. Forty-nine patients had no history of substance abuse or dependence but had other lifetime psychiatric diagnoses. Twenty-three patients had no history of substance abuse or psychiatric illness. No differences in demographic characteristics or in the features of chronic fatigue were found among the three groups. Patients with chronic fatigue who had a lifetime history of a substance use disorder reported more lifetime depressive symptoms and were more likely to have had suicidal ideation or attempts.