Objective. To compare efficacy and safety of metformin monotherapy and metformin in combination with melatonin concerning the parameters of endothelial function and the vascular elasticity, arterial hypertension (HTN), vascular premature aging and sleep status in patients with metabolic syndrome (MS). Design and methods. We performed an open prospective, comparative, controlled, randomized trial in 3 parallel groups. Altogether 238 patients with MS (IDF, 2005), HTN 1–2 degrees (who reached target blood pressure (BP) with the current antihypertensive therapy) and sleep disorders (< 19 scores by the survey of subjective sleep characteristics) were randomized into 3 groups. All patients underwent a lifestyle modification, including changesin diet and physical activity, as well as the normalization of the “sleep-wakefulness” rhythm for 12 weeks. In addition, patients of the first group (n = 80) received monotherapy with metformin, patients of the second group (n = 78) received combined therapy with metformin and prolonged-release melatonin. The control group (n = 80) included patients who adhere to the lifestyle modification recommendations without any pharmacological intervention. The groups were comparable for baseline clinical and demographic characteristics. At baseline and after 12 weeks of therapy the endothelial function was evaluated by flow-dependent vasodilation. Also BP, vascular stiffness, anthropometric and metabolic parameters, adipocytokine status, vascular age, and sleep quality were assessed. Results. The results of the study confirmed the efficiency of the long-acting melatonin in combination with the standard therapy in patients with MS and circadian disorders. Melatonin normalizes the “sleep-wakefulness” rhythm. Moreover, it provides protective effect regarding endothelial function, has favorable profile of cardiovascular and metabolic effects, and slows vascular aging. No serious drug-related adverse events were registered during the follow-up. Conclusions. Melatonin supplementation to the traditional MS therapy in patients with sleep disorders is safe and effective regarding dissomnia, overweight, metabolic disorders, and also has additional benefits in terms of improvement of endothelial function, vascular stiffness, and daily BP profile.