We undertook a study to investigate the therapeutic potential of orally administered melatonin in patients with advanced melanoma. Forty-two patients received melatonin in doses ranging from 5 mg/m2/day to 700 mg/m2/day in four divided doses. Two were excluded from analysis. After a median follow-up of 5 weeks, six patients had partial responses, six additional patients had stable disease. Sites of response included the central nervous system, subcutaneous tissue and lung. The median response duration was 33 weeks for the partial responders. There was a suggestion of a dose-response relationship. The toxicity encountered was minimal and consisted primarily of fatigue in 17 of 40 patients. Melatonin also appeared to reduce basal levels of follicle-stimulating hormone (FSH). No significant changes were encountered in serum levels of luteinizing hormone (LH) or thyroid stimulating hormone (TSH). We conclude that further study of melatonin as a potentially useful agent in metastatic melanoma is warranted.