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To compare one-stage vs. two-stage bilateral unicondylar knee arthroplasty (UKA) in terms of complications, mortality, reinterventions, transfusion rate, days to discharge, and outcomes for the treatment of bilateral mono-compartmental knee osteoarthritis.A systematic review was performed in the PubMed, Web of Science, and Cochrane databases up to February 2021. Randomized controlled trials, case-control studies, and case series describing the use of bilateral UKA were retrieved. A meta-analysis was performed on complications, mortality, reinterventions, transfusion rate, and days to discharge comparing one-stage vs. two-stage replacement, and outcomes were also reported. Assessment of risk of bias and quality of evidence was performed with the Newcastle-Ottawa Scale.Fifteen articles were included on 1451 patients who underwent bilateral UKA (44.9% men, 55.1% women, mean age 66 years). The systematic review documented, for bilateral one-stage UKA: 2.6% major and 5.4% minor complication rates, 0.5% mortality, 1.9% reintervention, 4.1% transfusion rates, and 4.5 mean days to discharge. No studies reported functional differences. The meta-analysis did not find differences for major complications, minor complications, mortality, reintervention, transfusion rates, or days to discharge versus two-stage bilateral procedures. The operative time was 112.3 vs. 125.4 minutes for one-stage and two-stage surgeries, respectively. The overall quality of the retrieved studies was high.Bilateral single-stage UKA is a safe procedure, with a few complications, and overall positive clinical results. No differences were found in terms of complications, mortality, reinterventions, transfusion rate, and days to discharge in comparison with the two-stage approach. Cite this article: EFORT Open Rev 2021;6:1063-1072. DOI: 10.1302/2058-5241.6.210047., Competing Interests: ICMJE Conflict of interest statement: All authors declare no support from any organization for the submitted work; Christian Candrian has received institutional support outside the present work from Medacta International SA, Johnson & Johnson, Lima Corporate, Zimmer Biomet, and Oped AG. Stefano Zaffagnini has received institutional support from Fidia Farmaceutici, Cartiheal, IGEA Clinical Biophysics, Biomet, and Kensey Nash. He has also received grant support from I+ and royalties from Springer., (© 2021 The author(s).)