Periprosthetic infection (PPI) is a difficult complication in total joint arthroplasty, and while erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are acute phase reactants thought to be of high predictive value for diagnosing infection, no clear cut-off values have been defined. The current study aimed to determine the cut-off values for ESR and CRP that improve clinical differentiation between aseptic failure and PPI in total hip arthroplasty (THA). Four hundred and seventy-nine patients who underwent revision THA for either aseptic mechanical failure or PPI during the period of 2000 to 2005 were included in the study. Specific exclusion criteria were applied to eliminate inflammatory or other confounding conditions. All patients underwent preoperative testing of ESR and CRP. Receiver operating characteristic (ROC) curves were constructed to determine maximum sensitivity and specificity. Patients with PPI had significantly higher ESR and CRP values compared to patients undergoing revision for aseptic etiologies. An ESR threshold of 30 mm/h gave a sensitivity of 94.3% and a CRP threshold of 10 mg/l gave a sensitivity of 91.1%. Combining both ESR and CRP cut-offs for a positive diagnosis increased the sensitivity to 97.6%. However, when calculated by ROC analysis, the predictive cut-offs equated to 31 mm/h for ESR and 20.5 mg/l for CRP. The gold standard for diagnosing PPI remains bacterial culture, but sensitivity is negatively affected by prior antibiotic exposure, strongly adherent bacteria, slow growing persisters, and biofilms. ESR and CRP are reflective of systemic changes in infection and pose an attractive, less invasive alternative with reasonable sensitivity and specificity. The current study is the first to identify ideal cut-off values for ESR and CRP in THA patients, providing an optimum balance between sensitivity and specificity based on ROC curves.