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Purpose Periprosthetic joint infection (PJI) is a catastrophic complication after total joint arthroplasty (TJA). Treatment of PJI is challenging, especially when causative microorganism is not identified. The purpose of this systematic review was to guide diagnostic approach and treatment of culture-negative (CN) PJI. Methods A systematic review was undertaken on clinical studies from MEDLINE, EMBASE, Cochrane Library, and Scopus databases. Basic science studies, letters, studies written in languages other than English, case reports,