Abstract Purpose Besides other diagnostic test methods, established serum inflammatory markers such as serum C-reactive protein or leukocyte count are widely used preoperatively to aid in diagnosing periprosthetic joint infections (PJI). Although low accuracies were reported, these parameters are easily accessible and routinely available. Novel biomarkers with promising results in diagnosing PJI (platelet count to mean platelet volume ratio) or other infectious conditions (percentage of neutrophils, neutrophils to lymphocytes ratio) were described. The purpose of this study was to investigate the diagnostic value of established and novel serum inflammatory biomarkers for the diagnosis of PJI so as to compare the results to find the serum inflammatory marker with the best performance. Methods In 177 patients with a previous total hip (n = 91) or knee (n = 86) arthroplasty and indicated revision surgery, the diagnostic value of the routinely available serum inflammatory markers C-reactive protein (CRP), white blood cell count (WBC), percentage of neutrophils (%N), neutrophils to lymphocytes ratio (NLR), fibrinogen and platelet count to mean platelet volume ratio (PC/mPV) were examined retrospectively via receiver operating characteristic curve analysis (AUC). The curves were compared using the z-test. Results Sensitivities of serum CRP, WBC, %N, NLR, fibrinogen and PC/mPV were calculated with 68%, 36%, 66%, 63%, 69% and 43%, respectively. Specificities were 87%, 89%, 67%, 73%, 89% and 81%, respectively. Serum CRP (0.78) and fibrinogen (0.79) showed significantly better AUCs compared with serum WBC (0.63), %N (0.67), NLR (0.68) and PC/mPV (0.62) (p < 0.0001). Patients with PJI caused by a low-virulent microorganism (median CRP: 17.6 mg/L) obtained lower CRP levels compared with infections caused by high-virulent microorganisms (median CRP: 49.2 mg/L; p = 0.044). The combination of CRP and fibrinogen showed a better sensitivity (77%) with similar specificity (83%) than one method alone but not at a significant level (CRP (p = 0.200); fibrinogen (p = 0.437)). Conclusion Serum CRP and fibrinogen showed the best accuracies among these widely available serum inflammatory parameters. However, due to the insufficient performance, these biomarkers can only be recommended as suggestive criteria in diagnosing PJI. The preoperative workup should always be complemented by more specific tests such as synovial fluid analysis.