Background: Post- operative prosthetic joint infection (PJI) is the most common cause of failure of total joint arthroplasty, requiring revision surgery, but a gold standard for the diagnosis and the consequent treatment of PIJ is still lacking. Among the scenario of infections diagnosis, an emerging molecule is Presepsin, the soluble fraction of CD14, recently described as a powerful diagnostic tool, not only to detect sepsis but also to discriminate different grade of sepsis severity. Question / purpose: We asked:1) is Presepsin a good diagnostic marker for PJI? 2) Does Presepsin correlate with other emerging infection markers such as TREM-1, CD-163, SuPAR, OPN and MMP-9, sTLR2 and CCL2 and IL-6?3) Is Presepsin a good prognostic marker of PJI? Methods: The population of 100 selected patients undergoing prosthesis revision was enrolled and subdivided into two groups: 48 patients having bacterial infection and 52 patients with no infection, undergoing aseptic loosening of the implant. CRP was measured using immunoturbidimetry on an automated biochemical analyzer (Olympus CRP-Latex assay, Central Valley, PA, CA, USA) Serum IL-6, TREM-1, CCL2, MMP-9, CD-163 and OPN were measured using an ELISA sandwich Quantikine Assay, while TLR2 was measured using an ELISA Duo Set Assay, according to manufacturer protocol (R&D System, Minneapolis, MN, USA). SuPAR was measured by SuPARnostic ELISA Assay, according to manufacturer protocol (Virogates, Denmark). Presepsin plasmatic levels were measured by Presepsin/ PATHFAST according to manufacturers’ protocol (Mitsubishi Chemical). PATHFAST Presepsin is a chemioluminescent enzyme immune assay (CLEIA) for the quantitative measurement of Presepsin concentration in whole blood or plasma. Results: Presepsin has a greater diagnostic value than CRP and IL-6 in the diagnosis of PJI, as assessed by ROC CURVE analysis. OPN, CCL2, TLR2 and SuPAR displayed good diagnostic values in PJI, while CD163, TREM-1 and MMP-9 displayed very low diagnostic potential. Presepsin, as well as OPN, CCL2, SuPAR and TLR2, displayed a significant decrease at the increasing time of recovery after surgery in PJI patients, while it remains unaltered and significantly lower (p<0.0001) in the patients undergone to revision surgery for aseptic loosening of the implant. These results clearly indicate that Presepsin have a good prognostic value, because it decreases gradually as the inflammatory process in response to the prosthetic infection is resolved. Conclusions: Taken together, these results indicate that Presepsin can be considered a useful tool for the diagnosis and clinical monitoring of PJI, and it can also be supported by a panel of new inflammatory makers involved in monocyte/macrophage mediated inflammatory response such as OPN, CCL2, TLR2 and SuPAR.