OBJECTIVE: Apart from regulating the circadian rhythm, melatonin exerts a variety of actions in the living organism. Among these functions, melatonin is believed to have a positive effect on body weight and energy metabolism. So far, the evidence for this relies mainly on animal models. In this study, we aimed to determine the effects of melatonin on body composition, lipid and glucose metabolism in humans. DESIGN/METHODS: In a double-blind, placebo-controlled study, we randomized 81 postmenopausal women to 1 year of treatment with melatonin (1 or 3 mg nightly) or placebo. Body composition was measured by DXA. Measures were obtained at baseline and after 1 year of treatment along with leptin, adiponectin and insulin. Markers of glucose homeostasis were measured at the end of the study. RESULTS: In response to treatment, fat mass decreased in the melatonin group by 6·9% (95% CI: 1·4%; 12·4%, P = 0·02) compared to placebo. A borderline significant increase in lean mass of 5·2% was found in the melatonin group compared to placebo (3·3%, (IQR:-1·7; 6·2) vs -1·9%, (IQR: -5·7; 5·8), P = 0·08). After adjusting for BMI, lean mass increased by 2·6% (95% CI: 0·1; 5·0, P = 0·04) in the melatonin group. Changes in body weight and BMI did not differ between groups. Adiponectin increased borderline significantly by 21% in the melatonin group compared to placebo (P = 0·08). No significant changes were observed for leptin, insulin or markers of glucose homeostasis. CONCLUSION: Our results suggest a possibly beneficial effect of melatonin on body composition and lipid metabolism as 1 year of treatment reduces fat mass, increases lean mass and is associated with a trend towards an increase in adiponectin.