OBJECTIVE: Melatonin has been widely studied in the treatment of sleep disorders and evidence is accumulating on a possible role for melatonin influencing mood. Our aim was to determine the efficacy and acceptability of melatonin for mood disorders. METHOD: We conducted a comprehensive systematic review of randomized clinical trials on patients with mood disorders, comparing melatonin to placebo. RESULTS: Eight clinical trials were included; one study in bipolar, three in unipolar depression and four in seasonal affective disorder. We have only a small study on patients with bipolar disorder, while we have more studies testing melatonin as an augmentation strategy for depressive episodes in major depressive disorder and seasonal affective disorder. The acceptability and tolerability were good. We analyzed data from three trials on depressive episodes and found that the evidence for an effect of melatonin in improving mood symptoms is not significant (SMD = 0.37; 95% CI [-0.05, 0.37]; P = 0.09). The small sample size and the differences in methodology of the trials suggest that our results are based on data deriving from investigations occurring early in this field of study. CONCLUSION: There is no evidence for an effect of melatonin on mood disorders, but the results are not conclusive and justify further research.