ObjectiveStem cell therapy is increasingly used for knee osteoarthritis (KOA). We aimed to review the evidence of autologous mesenchymal stem cell therapy on pain, function and severity on imaging in KOA.DesignSystematic review of randomised controlled trials (RCTs).Eligibility criteriaRCTs evaluating autologous mesenchymal stem cell (MSC) therapy on patient-reported outcome measures and disease severity.Data sourcesSeven databases were searched until 31 December 2020.Risk of bias and data synthesisRisk of bias was assessed using the ROB V.2. We used Grading of Recommendations Assessment, Development and Evaluation to appraise the certainty of the evidence. Data were synthesised descriptively.ResultsFourteen RCTs were included. A total of 408 patients with KOA received MSC therapy derived from bone marrow, adipose tissue or activated peripheral blood. After 1 year, 19 of 26 (73%) clinical outcome measures improved with MSCs compared with control. In the MSC group, patients improved by 1.8–4.4 points on the Visual Analogue Scale (0–10) and 18–32 points of the Knee Osteoarthritis Outcome Score (0–100). Four studies showed better disease severity on imaging after MSC compared with control at 1 year. Ten of 14 (71%) RCTs were at high risk of bias on all outcomes. No serious adverse events were reported after MSC therapy during a maximum of 4 years follow-up.ConclusionWe found a positive effect of autologous MSC therapy compared with control treatments on patient-reported outcome measures, and disease severity. The certainty of this evidence was low to very low.PROSPERO registration numberCRD42019120506