Objective: To explore the effect of granisetron, a 5-HT3 antagonist, on fatigue and functional impairment in patients with chronic fatigue syndrome (CFS). Methods: Five female patients were eligible to receive oral granisetron for one month (1 mg a day for the first two weeks and 2 mg a day for the second two weeks). The patients had to be between 18 and 65 years of age and suffering from CFS according to the CDC criteria. The effect was assessed by pre- and post-testing, using validated instruments designed to assess the different dimensions of CFS. Treatment response was also evaluated by visual analogue scales (VAS) for fatigue. Analysis was based on intention to treat. Results: Treatment with granisetron resulted in significant improvement in fatigue severity and functional impairment. Activity level showed no significant increase. Conclusion: The promising results of this study have encouraged us to perform a placebo-controlled, double-blind study to evaluate the efficacy of 5-HT3 receptor antagonists in the treatment of CFS.