OBJECTIVES: Cholangiocarcinoma is a leading cause of cancer death in the Northeast of Thailand. Currently, chemotherapy and supportive care are the main treatments in non-resectable cholangiocarcinoma patients. Many adverse events (AE) from disease and treatments have been reported that affect quality of life (QOL) of the patients. This study evaluated the efficacy of melatonin compared to placebo on the QOL, AE and survival time. METHODS: The study was a randomized, double-blind, placebo, controlled trial. The patients received treatment following the protocol of each hospital, and the study drug. Patients were randomized by mixed-block randomization stratified by hospital and type of treatment. The treatment group received melatonin (20 mg/day) and the control group received placebo. Patients started taking the study drug on the first day of the treatment and continued for three months. QOL was assessed using Thai Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-HEP) and AE were assessed using Common Toxicity Criteria Adverse Events (CTCAE). RESULTS: There were 30 patients recruited in the study, divided into 15 patients in each group. Baseline characteristics of the two groups were not different. The melatonin group had a higher but not significant percentage of improvement in FACT-Hep scores than the control in both the first (20% vs. 6.7%) and second (20% vs. 6.7%) month. Median survival was longer in the melatonin group (160 vs. 130 days, p>0.05). In addition, there were fewer reports of Grade 3-5 AE in the melatonin group than placebo in terms of anorexia (11% vs. 50%), fatigue (11% vs. 50%), nausea/vomiting (0% vs. 10%) and weight loss (0% vs. 20%). CONCLUSIONS: The combination of melatonin with standard treatment did not prolong overall survival. However, the melatonin treatment can decrease AE and maintain quality of life of non-resectable cholangiocarcinoma patients. Further studies with larger samples are needed.