Fatigue is a chronic and debilitating hallmark of the chronic fatigue syndrome, which is often accompanied by sleep disturbances, myalgias, and depression.1,2 This condition has been reported worldwide, and case definitions have been developed by the Centers for Disease Control and Prevention.3 Amantadine hydrochloride has been used to treat fatigue associated with conditions such as multiple sclerosis.4-6 We investigated the symptomatic effects of amantadine on 4 patients with chronic fatigue syndrome using a multiple single-subject trial design.7Patients who had a diagnosis of chronic fatigue made by their family physicians and who fulfilled the criteria for chronic fatigue syndrome defined by the Centers for Disease Control and Prevention were included.3 Using a multiperiod, crossover design,8 with a single subject for each sequence, patients received either placebo (B) or amantadine hydrochloride (A), 100 mg twice daily. Patients were blinded to treatment identification.