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Introduction: One in five patients undergoing total knee arthroplasty (TKA) experience unchanged or worse pain and physical function 1 year after surgery. Identifying risk factors for unfavourable outcomes is necessary to develop tailored interventions to minimise risk. There is a need to review more current literature with updated methodology that addresses the limitations of earlier systematic reviews and meta-analyses. We present a Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols compliant protocol for a systematic review and meta-analysis of predictors of chronic pain and impaired function after TKA., Methods and Analysis: This review will include prospective longitudinal observational studies, or randomised trials (including cluster and crossover designs) that report arm-wise predictors of chronic postsurgical pain or impaired physical function at 3 months, 6 months or 12 months. A comprehensive literature search of studies published between 2000 and 2019 will be performed in Medline, Embase, CINAHL, Cochrane Library and PEDro. Blinded assessment with consensus agreement will be applied for inclusion of studies, data extraction and assessment of bias risk (Quality in Prognosis Studies tool). The co-primary outcomes, pain and impaired function, at 12 months after TKA will be analysed separately. Estimates of association between each outcome and any preoperative or intraoperative factor that may predict chronic pain or impaired physical function will be extracted from the included studies, where possible. For randomised studies, results will only be extracted from TKA arms (or the first period of crossover trials). Estimates of association from the primary evidence will be synthesised narratively, and quantitatively using multivariate meta-analysis to provide 'pooled' estimates of association. Subgroup and sensitivity analyses will be performed. Certainty of evidence for each predictor will be derived from the Grading of Recommendations Assessment, Development and Evaluation framework., Ethics and Dissemination: No ethical issues are associated with this project. The results from this review will be published in peer-reviewed journals and presented at international conferences., Prospero Registration Number: CRD42018079069., Competing Interests: Competing interests: CJR reports personal fees from Oncolmmunity AS. He has a patent and patent application with no relevance to this study., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)