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Infection after shoulder arthroplasty can be a devastating complication, and subacute and chronic low-grade infections have proven difficult to diagnose. Serum marker analyses commonly used to diagnose periprosthetic infection are often inconclusive. The purpose of this study was to evaluate the effectiveness of serum interleukin-6 (IL-6) as a marker of periprosthetic shoulder infection.A prospective cohort study of thirty-four patients who had previously undergone shoulder arthroplasty and required revision surgery was conducted. The serum levels of IL-6 and C-reactive protein (CRP), the erythrocyte sedimentation rate (ESR), and the white blood-cell count (WBC) were measured. The definitive diagnosis of an infection was determined by growth of bacteria on culture of intraoperative specimens. Two-sample Wilcoxon rank-sum (Mann-Whitney) tests were used to determine the presence of a significant difference in the ESR and WBC between patients with and those without infection, while the Fisher exact test was used to assess differences in IL-6 and CRP levels between those groups. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of each marker were also calculated.There was no significant difference in the IL-6 level, WBC, ESR, or CRP level between patients with and those without infection. With a normal serum IL-6 level defined as <10 pg/mL, this test had a sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 0.14, 0.95, 0.67, 0.61, and 0.62, respectively.IL-6 analysis may have utility as a confirmatory test but is not an effective screening tool for periprosthetic shoulder infection. This finding is in contrast to the observation, in previous studies, that IL-6 is more sensitive than traditional serum markers for periprosthetic infection.Diagnostic Level II. See Instructions for Authors for a complete description of levels of evidence.