BACKGROUND: The aim of this meta-analysis was to investigate the efficacy and safety of intra-articular injection of mesenchymal stem cells (MSCs) alone for the treatment of unoperated knee osteoarthritis (OA). METHODS: Four databases were systematically searched (before August 1, 2024) to include randomized controlled trials (RCTs) of MSCs for OA. The population of this study was OA patients who had not received any surgical treatment. The intervention was intra-articular injection of MSCs without other adjuvant therapy. Outcomes included Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), 100-mm Visual Analog Score (VAS), Knee Injury and Osteoarthritis Prognostic Score (KOOS), and adverse events. After screening the literature according to the eligibility criteria, extracting the data, and evaluating the quality, Meta-analysis was performed using Revman 5.3 software. The review was conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. RESULTS: 8 RCTs and 502 patients with OA were included in the study. Compared with the control group, MSCs significantly improved 6-month WOMAC [MD = 7.44, 95% CI = (1.45, 13.42), P = 0.01] and 12-month WOMAC [MD = 10.31, 95% CI = (0.96, 19.67), P = 0.03]. MSCs also improved VAS and KOOS at 6 and 12 months in patients with OA. Subgroup analysis showed more significant efficacy of adipose source and high doses of MSCs. There was no significant difference between the adverse events in the MSCs group and the control group (P >
0.05). CONCLUSION: Intra-articular injection of MSCs alone could significantly improve knee pain and dysfunction in patients with unoperated OA. MSCs are expected to be an effective treatment for OA with enhanced delivery efficiency.