While psychoeducational strategies and general support are always indicated for the treatment of chronic fatigue syndrome (CFS), pharmacological strategies are yet not well established. Antidepressants such as selective serotonin re-uptake inhibitors have been shown to influence positively symptoms and immunological parameters. However, a considerable part of CFS patients do not satisfactorily respond to them. Bupropion, a centrally acting catecholamine-transporter blocker without classic psycho-analeptic properties, shows theoretical potential to improve fatigue symptoms. In the reported case paroxetine was augmented with bupropion at high dosage, a strategy which consecutively led to a rapid relief of CFS-symptoms.