e24087 Background: Cancer-related fatigue (CRF) is one of the most common symptoms reported and is estimated to affect up to 90% of cancer patients during the course of the disease. CRF may persist even after the end of cancer treatment. There is no definitive effective treatment with a high level of evidence and several alternatives have been sought after to aid traditional medications, with emphasis on natural supplements as a form of adjuvant treatment. In previous studies carried out by the Department of Oncology at ABC Medical School, a purified extract of Guarana ( Paullinia cupana), a plant native to the Amazon, showed promising results in clinical trials with patients undergoing chemotherapy, but with a limited number of patients and, thus, lower level of evidence. Therefore, the present study carried out a systematic review and meta-analysis of the supplementation of Guarana and its derivatives to combat CRF to produce more robust evidence regarding its possible therapeutic effect. Methods: Systematic review with meta-analysis registered at the International Prospective Register of systematic reviews (PROSPERO) under code CRD42023484144. Two independent researchers searched for articles in English on PUBMED, MEDLINE and Cochrane Library using controlled vocabulary (MeSH terms) and keywords related to CFR, Guarana and its related terms. Eligible studies were selected based on predefined criteria and were assessed for quality according to Cochrane Handbook for Systematic Reviews of Interventions. Data extraction was independently performed by two reviewers – any discrepancies were resolved by a third researcher. On the rare occasions in which a study was published as an abstract and then published as a full article, only its complete version was considered eligible for inclusion to avoid duplicates and reduce risk of bias. All analyses were conducted with RevMan 5.4.1 and employed random-effects model. Results: Of the 117 articles found, 4 full articles and 1 abstract were added to the meta-analysis, comprehending a total of 229 patients and the years of 2007-2023. With high heterogeneity between studies (I² = 78%, Chi² = 18.51, df = 4, P = 0.0010), our analysis found benefit in using guarana to combat CRF: Standard Mean Difference -0.77 (IC95% -1.34; -0.21), Test for overall effect: Z = 2.68 (P = 0.007). Conclusions: Our analysis supports the use of Guarana to combat Cancer-Related Fatigue. Further investigation with prospective randomized controlled trials should be carried out to validate our findings.