Two-stage exchange arthroplasty remains the treatment of choice for chronic periprosthetic joint infections. This retrospective study conducted between 2009 and 2015 examined the diagnostic value of biomarkers for residual infection between stages. The biomarkers evaluated included C-reactive protein prior to reimplantation, preimplantation synovial fluid white blood cell count and percent neutrophils, and the intraoperative histologic synovial white blood cell count per high-power field (×400) on permanent sections. Residual infection was defined as either positive cultures (more than 1) at second stage, any further surgery (eg, amputation, arthrodesis, or another 2-stage revision), or the need for infection suppression with antibiotics. Sensitivity, specificity, positive and negative predictive values, and likelihood ratios were calculated accordingly. A total of 182 two-stage exchange operations that included 109 (59.9%) prosthetic hips and 73 (40.1%) prosthetic knees met the inclusion criteria. Residual infection was present in 38 (20.9%) of the procedures. The area under the curve-receiver operating characteristic values were 0.677 for C-reactive protein (P=.002), 0.506 for aspiration white blood cell count (P=.944), 0.623 for aspiration percent neutrophils (P=.200), and 0.524 for white blood cell count per high-power field (P=.801). Positive and negative predictive values were poor and ranged between 26% and 57% and 78% and 85%, respectively. Analyses using specific combinations of biomarkers did not significantly improve predictive values. This study showed that classic markers perform poorly in identifying residual infection prior to second-stage revision. Further research is necessary to evaluate the diagnostic utility of other, more recently introduced biomarkers to determine whether infection has been eradicated between stages.