To evaluate the efficacy and safety of intra-articular mesenchymal stromal cell (MSC) injections for knee osteoarthritis (OA) treatment. We performed a systematic literature search in PubMed, Embase, Scopus and the Cochrane Library through April 2020 to identify Level I randomized controlled trials (RCTs) that evaluated the clinical efficacy of MSC versus control treatments for knee OA. Outcomes were analyzed on an intention-to-treat basis with random-effects models. A total of 13 RCTs were included in the meta-analysis. Compared with the placebo, there was no significant difference about VAS for pain (mean differences [MD]: 1.62, 95% confidence intervals [CI]: -0.60 to 3.85), WOMAC pain score (MD: 1.88, 95% CI: -0.21 to 3.98), WOMAC function score (MD: -0.67, 95% CI: -6.54 to 5.19), and WOMAC stiffness score (MD: 0.64, 95% CI: -0.86 to 2.14) for MSC. Moreover, the smallest treatment effect of VAS for pain, WOMAC pain score, WOMAC function score, and WOMAC stiffness score did not exceed their minimum clinically important differences (MCID). Additionally, there was no significant difference in percentage of patients crossing the MCID threshold between MSC and placebo groups for VAS for pain (relative risk [RR]: 0.93, 95% CI: 0.55 to 1.57) and WOMAC total score (RR: 0.40, 95% CI: 0.13 to 1.21). Compared with the hyaluronic acid (HA), MSC was associated with significantly better improvement in VAS for pain (MD: 2.00, 95% CI: 0.94 to 3.07), WOMAC pain score (MD: 4.58, 95% CI: 0.49 to 8.67), WOMAC total score (MD: 14.86, 95% CI: 10.59 to 19.13), and WOMAC stiffness score (MD: 1.85, 95% CI: 0.02 to 3.69). However, the smallest treatment effect of VAS for pain, WOMAC pain score, WOMAC function score, and WOMAC stiffness score did not exceed their MCID. Moreover, there was no significant difference in percentage of patients crossing the MCID threshold between MSC and HA groups for WOMAC total score (RR: 0.57, 95% CI: 0.21 to 1.55). We also found MSC did not increase adverse events compared with HA and placebo. Intra-articular MSC injection was not found to be superior to placebo in pain relief and functional improvement for patients with symptomatic knee OA. However, additional direct testing and combination trials of different type of cells, doses, and number of injections of MSC are required to further enhance clinical decision making for people with symptomatic knee OA. Copyright © 2020. Published by Elsevier Inc.