Accurate preoperative diagnosis of periprosthetic joint infections (PJIs) can be very challenging, especially in patients with chronic PJI caused by low-virulence microorganisms. Serum parameters, such as serum C-reactive protein (CRP) or the erythrocyte sedimentation rate (ESR), are—among other diagnostic test methods—widely used to distinguish septic from aseptic failure after total hip or knee arthroplasty and are recommended by the AAOS in the preoperative setting. However, they are systemic parameters, and therefore, unspecific. Nevertheless, they may be the first and occasionally the only preoperative indication, especially when clinical symptoms are lacking. They are easy to obtain, cheap, and are available worldwide. In the last decade, different novel serum biomarkers (percentage of neutrophils, neutrophils to lymphocytes ratio, platelet count to mean platelet volume ratio, fibrinogen, D-Dimer, Il-6, PCT) were investigated to find a more specific and accurate serum parameter in the diagnosis of PJI. This article reviews the diagnostic value of established (serum CRP, ESR, WBC) and ‘novel’ serum inflammatory biomarkers (fibrinogen, D-dimer, interleukin-6 (IL-6), procalcitonin, percentage of neutrophils (%N), neutrophils to lymphocytes ratio (NLR), platelet count to mean platelet volume ratio (PC/mPV)) for the preoperative diagnosis of periprosthetic joint infections.