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Background: Diagnosis of periprosthetic joint infection (PJI) in patients undergoing revision shoulder arthroplasty is challenging because of the low virulence of the most common infecting organisms. The goal of this study was to evaluate the diagnostic utility of measuring synovial fluid interleukin-6 (IL-6) levels for identifying PJI of the shoulder. Methods: Thirty-two consecutive patients evaluated for pain at the site of a shoulder arthroplasty were prospectively enrolled from November 2012 to September 2013 and underwent revision surgery (thirty-five procedures during which samples were obtained for synovial fluid IL-6 analysis). Cases were categorized into infection (n = 15) and no-infection (n = 20) groups on the basis of objective preoperative and intraoperative findings. Twenty patients treated with arthroscopic rotator cuff repair were also enrolled to serve as a non-infected control group. Synovial fluid was obtained through aspiration intraoperatively for all patients, as well as preoperatively for some. Synovial fluid IL-6 levels were measured with use of a cytokine immunoassay that utilizes electrochemiluminescent detection. A receiver operating characteristic curve was used to determine the diagnostic utility of synovial fluid IL-6 analysis. Results: Based on receiver operating characteristic curve analysis, synovial fluid IL-6 measurement had an area under the curve of 0.891 with an ideal cutoff value of 359.3 pg/mL. The sensitivity, specificity, and positive and negative likelihood ratios were 87%, 90%, 8.45, and 0.15, respectively. Seven patients who underwent a single-stage revision had negative results on standard perioperative testing, including the erythrocyte sedimentation rate and C-reactive protein levels, but multiple positive intraoperative tissue cultures. The level of synovial fluid IL-6 was elevated in five of these seven patients, with a median value of 1400 pg/mL. Intraoperative synovial fluid IL-6 values correlated well with preoperative IL-6 synovial fluid values (correlation = 0.61; p = 0.025) and frozen-section histologic findings (p < 0.001). Synovial fluid IL-6 levels were also significantly elevated in patients with Propionibacterium acnes infection (p = 0.01). Conclusions: Measurement of synovial fluid IL-6 levels is more sensitive and specific than current preoperative testing for predicting positive cultures for patients undergoing revision shoulder arthroplasty. This diagnostic accuracy can lead to improved decision-making in the management of PJI. Level of Evidence: Diagnostic Level II. See Instructions for Authors for a complete description of levels of evidence. [ABSTRACT FROM AUTHOR]