RATIONALE: Preserving health-related quality of life is an aspect of care that requires constant attention from the time of cancer diagnosis. Melatonin has been used to diminish treatment-related side effects and cancer symptoms, and as a medication to regulate circadian rhythm. An up-to-date systematic review is needed to investigate the current evidence concerning possible beneficial effects of melatonin on quality of life and sleep in cancer patients. OBJECTIVES: To evaluate the benefits and harms of melatonin for preserving health-related quality of life and sleep in cancer patients. SEARCH METHODS: To identify studies for inclusion in this review, we used CENTRAL, MEDLINE, 10 other databases, and four trial registers, together with reference checking, citation searching, and contact with study authors. The latest search date was 10 September 2024. ELIGIBILITY CRITERIA: We included randomised controlled trials (RCTs) of adults (18 years or over) with histologically proven cancer of any stage that evaluated melatonin (alone or in combination with standard anticancer treatment) versus no treatment or placebo (alone or in combination with standard anticancer treatment), or standard anticancer treatment. Standard anticancer treatment refers to treatments to stop or prevent cancer, including chemotherapy, radiation therapy, surgery, immunotherapy, and hormonal therapies (such as androgen deprivation therapy). OUTCOMES: The primary outcomes of interest were quality of life and sleep quality within three months, and melatonin-related adverse events. Other outcomes included survival, disease-free survival, progression-free survival, tumour response, and anticancer treatment-related harms. RISK OF BIAS: We used Cochrane's risk of bias tool (RoB 1) to assess the risk of bias in the studies included in the review. SYNTHESIS METHODS: We synthesised results for each outcome using random-effects meta-analysis. The effect size was presented as risk ratio (RR) for dichotomous data and mean difference (MD) for continuous data, with 95% confidence intervals (CI). If this was not possible, due to the nature of the data, we synthesised results in a narrative format. We used GRADE to assess the certainty of evidence for each outcome. INCLUDED STUDIES: We identified 30 RCTs (reported in 49 publications) involving 5093 adult participants with cancer (2470 males, 2228 females, 395 not reported). Studies were conducted in a hospital setting and took place in at least 10 countries. We assessed two studies at low risk of bias and the other 28 at high risk of bias. SYNTHESIS OF RESULTS: Melatonin plus standard treatment versus placebo plus standard treatment The evidence is very uncertain about the effect of melatonin on quality of life score (MD 2.60, 95% CI -14.53 to 19.73; 1 study, 126 participants; very low certainty evidence), and sleep score (MD 2.80, 95% CI 0.18 to 5.42; 1 study, 50 participants; very low certainty evidence) within three months. We are also very uncertain about potential adverse effects of melatonin: headache (RR 2.77, 95% CI 0.33 to 23.14; 1 study, 25 participants; very low certainty evidence); fatigue (RR 1.02, 95% CI 0.90 to 1.17; 2 studies, 170 participants; very low certainty evidence); and nausea (RR 1.01, 95% CI 0.66 to 1.56; 1 study, 146 participants; very low certainty evidence). No data are available relating to dizziness. We downgraded the certainty of the evidence because of high risk of bias, small sample size, the width of the 95% confidence interval, and indirectness due to inadequate reporting of cancer type. Melatonin plus standard treatment versus standard treatment No data are available relating to quality of life and sleep within three months. The evidence is very uncertain about headaches (experienced by 15 of 820 participants in melatonin groups, with no data available for control groups; 2 studies, 1640 participants; very low certainty evidence). Melatonin likely reduces the incidence of fatigue (RR 0.46, 95% CI 0.39 to 0.55; 10 studies, 1359 participants; moderate-certainty evidence) and may reduce nausea (RR 0.85, 95% CI 0.72 to 1.00; 6 studies, 710 participants; low-certainty evidence). No data are available relating to dizziness. We downgraded the certainty of the evidence because of the high risk of bias and the width of the 95% confidence interval. Melatonin (topical use) plus standard treatment versus placebo plus standard treatment The evidence is very uncertain about the effect of melatonin on quality of life (one study reported no difference between groups, both having the same median score of 66.7; 48 participants; very low certainty evidence). No data are available relating to sleep and adverse events (including headache, dizziness, fatigue, and nausea). We downgraded the certainty of the evidence because of the high risk of bias, small sample size, and insufficient data. AUTHORS' CONCLUSIONS: The available evidence is of very low certainty, so we are unable to draw conclusions about the effects of melatonin on quality of life and sleep at three months in people receiving treatment for cancer. There may be no difference in adverse events between melatonin plus standard treatment and placebo plus standard treatment, but the evidence is very uncertain. Data were lacking for some outcomes, such as dizziness. Melatonin used alongside standard treatment probably reduces the risk of fatigue and may reduce nausea when compared to standard treatment alone. Since the evidence base for melatonin in people with cancer is limited due to insufficient data and risks of bias in study design, the decision for or against using melatonin as an adjunct to cancer treatment cannot easily be made at the current time. FUNDING: This Cochrane Review was partially funded by AG Biologische Krebstherapie, Deutsche Krebshilfe (grant numbers 70-301 and 109863). The funding agency had no role in the design or conduct of the study. REGISTRATION: The protocol for this review is available via DOI 10.1002/14651858.CD010145.