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The role and diagnostic value of the synovial complement system in patients with low-grade periprosthetic joint infection (PJI) are unclear. We sought to evaluate, for the first time, the usefulness of synovial complement factors in these patients by measuring the individual synovial fluid levels of complement factors (C1q, C3b/iC3b, C4b, C5, C5a, C9, factor B, factor D, factor H, factor I, properdin, and mannose-binding lectin [MBL]). The patients (n = 74) were classified into septic (n = 28) and aseptic (n = 46). Receiver-operator characteristic curves and a multiple regression model to determine the feasibility of a combination of the tested cytokines to determine the infection status were calculated. The synovial fluid levels of C1q, C3b/C3i, C4b, C5, C5a, MBL, and properdin were significantly elevated in the PJI group. The best sensitivity and specificity was found for C1q. The multiple regression models revealed that the combination of C1q, C3b/C3i, C4b, C5, C5a, and MBL was associated with the best sensitivity (83.3%) and specificity (79.2%) for a cutoff value of 0.62 (likelihood ratio: 4.0; area under the curve: 0.853). Nevertheless, only a combined model showed acceptable results. The expression patterns of the complement factors suggested that PJI activates all three pathways of the complement system.