Several experimental studies have shown that melatonin has an oncostatic action, either by stimulating host antitumor immune defenses or by directly inhibiting the growth of some cancer histotypes, including melanoma. Our previous clinical studies demonstrated that melatonin may induce stabilization of the disease in untreatable metastatic solid tumor patients, and these results have been confirmed by others, at least in patients with metastatic melanoma. On the contrary, at present there are no data related to the possible efficacy of melatonin as an adjuvant endocrine therapy. This study was performed to investigate the impact of melatonin therapy on the disease-free survival (DFS) in melanoma patients surgically treated for regional node recurrence. The study included 30 node-relapsed melanoma patients, who were randomized to receive no treatment or adjuvant therapy of melatonin (20 mg/day orally in the evening) every day until disease progression. After a median follow up of 31 months, the percent of DFS was significantly higher in melatonin-treated individuals than in controls. The DFS curve was also significantly longer in melatonin group than in controls. No melatonin-related toxicity was observed. This preliminary study suggests that an adjuvant endocrine therapy with melatonin may be effective in preventing disease progression in node-relapsed melanoma patients.