Background: Fatigue is a common complaint that may lead to long-term sick leave and work disability. Aims: To assess the efficacy of cognitive- behavioural therapy by general practitioners for unexplained, persistent fatigue among employees. Method: A randomised controlled trial, using a pre-randomisation design in primary care, investigated 151 employees on sick leave with fatigue. Participants in the experimental group were offered five to seven 30 min sessions of cognitive-behavioural therapy by a general practitioner; those in the control group were offered no treatment. Main outcome measures (fatigue severity, self-reported absenteeism, registered absenteeism and clinical recovery) were assessed at 4 months, 8 months and 12 months. Results: At baseline, 44% of the patients already met research criteria for chronic fatigue syndrome. There was no significant difference between the experimental group and the control group on primary or secondary outcomes at any point. Conclusions: Cognitive-behavioural therapy by general practitioners for unexplained, persistent fatigue did not prove to be an effective intervention. Since these doctors were unable to deliver this therapy effectively under ideal circumstances, it is unlikely that doctors in routine practice would be more successful in doing so.