Background: Knee osteoarthritis (OA) is a major cause of disability among the older adults.Few treatments are safe and effective.Moxibustion is commonly used in treating knee OA in Chinese medicine (CM).CO2 Laser moxibustion device is a substitute for traditional moxibustion,which mimics the effects of traditional moxibustion.More data are needed to support its application in knee OA.Objective: The trial aims to assess the effect and safety of CO2 laser moxibustion in patients with knee osteoarthritis compared with a sham control.Methods: This is a protocol for a multicenter,randomized,double-blind,placebo-controlled tdal.A total of 392 participants were recruited and assigned to the CO2 laser moxibustion group and sham laser moxibustion group with a 1:1 ratio at 6 outpatient clinics in Shanghai,China.Participants in both groups received treatment at the affected knee(s) at the acupuncture point Dubi (ST 35) and an Ashi point.There were 3 sessions per week for 4 weeks,and an additional 20-week follow-up.Primary outcomes were changes in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain scores at week 4.Secondary outcomes were WOMAC function score,stiffness score and overall score,VAS pain,Short-Form heath survey (SF-36),and patients\' global assessment.The serum levels of cytokines involved in progress of knee OA were explored.Safety was assessed during the whole trial.Masking effectiveness was assessed by both participants and treatment providers.Discussion: CO2 laser moxibustion device,designed as a substitute for CM moxibustion,is easy to use and control with no choking smoke and smell,and is a plausible method for double-blind research.This study would provide rigorous evidence for the effect and safety of CO2 laser moxibustion in treating knee OA (Trial registration No.: ISRCTN15030019).