Background: We aimed to explore the feasibility of evaluating effectiveness and safety of electroacupuncture (EA) for the treatment of knee osteoarthritis (KOA) based on different meridian syndromes. Methods: A multicenter randomized controlled trial was conducted in Beijing from January 2019 to December 2019. Sixty KOA participants were randomly allocated to either EA (n=30) or SA (n=30) groups. Participants in EA group were treated with semi-standardized on different meridian syndrome, including five obligatory acupoints and three adjunct acupoints. Eight non-acupoints that were separated from conventional acupoints or meridians were used for the SA group. Both groups received 24 sessions within eight weeks. The primary outcome was response rate, defined as a change of >= 50% from baseline in total scores of Western Ontario and McMaster Universities osteoarthritis index (WOMAC) at the end of treatment. Secondary outcomes included function, pain, stiffness, quality of life and acupuncture-related adverse events at four and eight weeks. Results: Of 60 participants randomized, 56 (93.3%) completed the study. Response rates were 60% for the EA group and 30% for the SA group after eight weeks. Significant differences were observed in WOMAC pain and total scores within two groups (P=0.026, P=0.043). Rates of adverse events were low and similarly distributed between groups. Conclusion: EA intervention based on meridian differentiation in KOA was feasible and appeared safe, having a stronger impact on pain than SA. Future studies can be designed with larger sample size, adequately powered, randomization design and less biases.