Shuai Dong,1 Lan-Xin Wang,2 Qing-Yu Yu,3 Duan-Yu Mou,2 Dong-Sheng Qiu,4 Guo-Ping Ye,4 Xi Wu1 1College of Acupuncture and Tuina, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, People’s Republic of China; 2Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 610075, People’s Republic of China; 3The First Clinical Medical College, Beijing University of Chinese Medicine, Beijing, 100029, People’s Republic of China; 4Xiamen TCM Hospital Affiliated to Fujian University of Traditional Chinese Medicine, Xiamen, Fujian, 361015, People’s Republic of ChinaCorrespondence: Guo-Ping Ye, Xiamen TCM Hospital Affiliated to Fujian University of Traditional Chinese Medicine, Xiamen, Fujian, 361015, People’s Republic of China, Email 810626322@qq.com Xi Wu, College of Acupuncture and Tuina, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, People’s Republic of China, Email wuxi@cdutcm.edu.cnIntroduction: Knee osteoarthritis (KOA) is a prevalent degenerative joint disease that severely undermines the quality of life in middle-aged and elderly people. Pain is the predominant clinical symptom of KOA. Existing pharmacological treatments often cause side effects including gastrointestinal damage and cardiovascular complications. Common non-pharmacological interventions like exercise therapy also fail to achieve satisfactory clinical outcomes with limited curative effect. As a classic external therapy in traditional Chinese medicine, bloodletting therapy (BLT) has gradually demonstrated promising value in the clinical management of KOA. Despite its growing application, there still lacks systematic evidence-based evaluation on the overall efficacy and safety of BLT for KOA treatment, which restricts its standardized clinical promotion and popularization.Purpose: This study aimed to systematically evaluate the efficacy and safety of BLT in the treatment of KOA and provide the best current evidence for clinical practice.Patients and Methods: This study followed the PRISMA guidelines (2020) and systematically retrieved randomized controlled trials (RCTs) from three Chinese databases, two English databases, and one trial registry as of July 10, 2025. The inclusion criteria included adult patients with KOA, BLT as the intervention measure (either alone or in combination), and RCTs comparing it with Western medicine, Western medicine plus rehabilitation, acupuncture, etc. The primary outcome was pain intensity (VAS/WOMAC); the secondary outcomes included inefficient rate (inefficient rate= Ineffective/total number of participants× 100%), response rate (response rate = (clinical control+ apparent effect) / total number of participants× 100%), quality of life (SF-36) and adverse reactions. The risk of bias was evaluated using the Cochrane ROB 2.0 tool, and a Meta-analysis was conducted using RevMan 5.4.1. The quality of evidence was assessed using the GRADE tool.Results: A total of fifteen RCTs involving 1108 patients were included. The types of BLT included picking BLT, wet cupping, and Zhuang medicine BLT. The most commonly used BLT acupoint is the Ashi point. The comparison types included BLT vs. Drugs (n=4), BLT plus drugs vs. Drugs (n=1), BLT plus drugs and rehabilitation vs. Drugs plus rehabilitation (n=1), BLT plus drugs vs. Drugs plus rehabilitation (n=1), and BLT plus acupuncture vs. acupuncture (n=8). Of all included trials, one was assessed as “low risk of bias”, one was rated as “high risk of bias” and thirteen were assessed as “some concern”. The results showed that BLT improved the response rate by 23% compared with drugs (sodium hyaluronate and ibuprofen tablets) alone. BLT plus rehabilitation reduced the pain intensity by 13.31 scores in the WOMAC and increased the response rate by 80% compared with drugs (diclofenac sodium sustained-release tablets) plus rehabilitation. BLT plus acupuncture alone reduced the inefficient rate by 74%, improved the response rate by 44%, and improved the quality of life score (SF-36 scale) by 50.40 scores, and the subgroup analysis showed that when there were fewer bloodletting locations, the better the pain relief effect. BLT plus acupuncture may increase the risk of adverse effects compared with acupuncture alone. The quality of the evidence was generally low or very low, mainly due to methodological limitations and heterogeneity.Conclusion: Current very low-quality evidence suggests that BLT alone or combined with acupuncture, drugs and rehabilitation, and drugs may have certain advantages in alleviating KOA pain, reducing inefficient rate, and increasing response rate. Compared with acupuncture, BLT plus acupuncture may increase the risk of adverse reactions. However, due to the low methodological quality of the included studies, the conclusion should be interpreted with caution. Future studies with higher quality and larger sample sizes are needed to further verify its efficacy and safety.Keywords: bloodletting, osteoarthritis, knee, efficacy, safety