BACKGROUND: In this study, we evaluated whether platelet-rich plasma (PRP) is superior to hyaluronic acid (HA) in the treatment of knee osteoarthritis. METHODS: The Cochrane Central Register of Controlled Trials, PubMed, and Embase databases were searched for English-language, human in vivo studies on the treatment of symptomatic knee osteoarthritis with intra-articular PRP compared with HA. The following keywords were used for the search: "platelet-rich plasma," "PRP," "platelet-rich fibrin," "PRF," "platelet," "plasma," "arthritis," "osteoarthritis," "gonarthrosis," and "degeneration." RESULTS: Seven articles reporting 908 patients and 908 knees were analyzed, including 44% men and 56% women with a mean age of 59.8 years. All studies met the minimal clinically important difference criteria and showed statistically significant improvements in clinical outcomes, including pain, physical function, and stiffness, with PRP treatment. All except two studies showed significant differences between PRP and HA regarding clinical outcomes of pain and function. CONCLUSIONS: PRP intra-articular injection of the knee may be an effective alternative treatment for knee OA, especially in patients with mild knee OA. Although some studies suggested that the effect of PRP was no better than HA, we found that it was no worse. A large, multicenter, randomized trial is needed to further assess the efficacy of PRP treatment for patients with knee OA. TRIAL REGISTRATION: PROSPERO, CRD42016048394 . Registered on October 2, 2016).