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The authors describe the first case of Weissella confusa infection of a prosthetic joint. Identification of the pathogen required 16S ribosomal RNA sequencing of isolates obtained on two separate occasions during the assessment of an elderly woman with a painful, swollen knee following total knee arthroplasty. A review of reported human infections due to W confusa are summarized, and risk factors and pitfalls in the application of empirical antimicrobial therapy pending definitive microbiological identification are discussed.