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There is a strong association between the chronic fatigue syndrome and both depressive illness and sleep disturbance, but the efficacy of antidepressants is uncertain. We studied the efficacy and adverse effects of moclobemide in patients with chronic fatigue syndrome, stratifying the sample both by co-morbid major depressive illness and by sleep disturbance. Forty-nine patients with chronic fatigue syndrome were recruited. Patients were given moclobemide up to 600 mg a day for 6 weeks. Four (8%) patients dropped out, three because of adverse effects. Adverse effects were otherwise mild and transient. On analysing the whole sample, there were significant but small reductions in fatigue, depression, anxiety and somatic amplification, as well as a modest overall improvement. The greatest improvement occurred in those individuals who had a co-morbid major depressive illness, with seven out of 14 (50%) of such individuals rating themselves as “much better” by 6 weeks, compared to six out of 31 (19%) of those who were not depressed (31% difference, 95% CI 1–60%, P = 0.04). Sleep disturbance had no effect on outcome. Moclobemide may be indicated in patients with chronic fatigue syndrome and a co-morbid major depressive disorder. A randomized, placebo-controlled trial is needed to confirm this. These results do not support moclobemide as an effective treatment of chronic fatigue syndrome in the absence of a major depressive disorder.