Fatigue is a common reason for consulting a doctor but there is no definitive treatment. Hypericum perforatum has been shown to reduce symptoms of fatigue in depressed patients. It therefore may have potential value as a remedy for fatigue of unexplained origin. This pilot study aimed to investigate the effect of Hypericum on fatigue in a small group of patients in order to formulate a hypothesis upon which a randomized controlled trial could be subsequently based. The study protocol followed an uncontrolled, open design. Twenty patients consulting their doctors complaining of fatigue were treated with Hypericum extract (3×1 tablet daily) for six weeks. Compared to baseline values, perceived fatigue was significantly lower after 2 weeks of treatment and reduced significantly further after 6 weeks. Symptoms of depression and anxiety were also reduced. Baseline scores suggested that nearly half the sample may have been depressed at the start of the trial which was possibly related to fatigue. These results suggest there is scope for conducting a randomized placebo-controlled trial to investigate the specific effect of Hypericum on fatigue and that the study design must take account of the role of depression in fatigue.