The recent advances in the psychoneuroimmunology have suggested that the hematopoiesis may be under a neuroendocrine regulation, mainly exerted by the pineal gland. In particular, melatonin (MLT), which is the main pineal hormone, has appeared to stimulate platelet generation, probably by promoting the megakaryocyte fragmentation and modulating the cytokine network involved in platelet production. On this basis, we have evaluated the effect of pharmacological doses of MLT on platelet number in patients with persistent thrombocytopenia due to different causes. The study included 200 patients, who were randomized to receive supportive care alone or MLT at 20 mg/day orally in the evening, for al least 1 month. No MLT-related toxicity occured. Platelet mean number rapidly and significantly increased in response to MLT, and a normalization of platelet number was achieved on MLT therapy in 71/98 (72%) patients. The least responsive form of thrombocytopenia was DIC. This study shows that the pineal hormone MLT may represent a well tolerable and effective therapy of thrombocytopenia due to different pathogenetic mechanisms.