C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), plasma fibrinogen and D-Dimer are used as diagnostic biomarkers of prosthetic joint infection (PJI) after total joint arthroplasty (TJA). The purpose of the study was to investigate the normal trajectory of CRP, ESR, plasma fibrinogen and D-Dimer at different time points after two-stage exchange arthroplasty for PJI.We studied 53 patients undergoing two-stage exchange for PJI at five time points: preoperatively (T0), duration of hospital stays (T1), 30 days (T2), 30-90 days (T3), and 90-180 days (T4) after surgery. The medical records of all patients were well documented and carefully reviewed. The Shapiro-Wilk test was utilized to compare the normal distribution for continuous variables, and the nonnormally distributed data were used for Friedmann's one-way repeat measures analysis of variances. Post hoc Dunnett's test was used to compare each pair of data to find differences from baseline.Compare with T0 point, the levels of CRP and ESR increased significantly and reached peak values at T1 point (all P 0.001), with median values of 56.40 mg/L (range, 5.54-161.0 mg/L) and 49.00 mm/h (range, 13.00-113.0 mm/h), respectively. In addition, the levels of plasma fibrinogen and D-Dimer increased significantly and reached peak values at T1 point (all P 0.001), with median values of 4.13g/L (range, 2.27-6.80 mg/L) and 4.00 mg/L (range, 0.19-14.01 mg/L), respectively. CRP and ESR rapidly declined at the T2 point with significantly compared with T0 point (P = 0.001 and P 0.001). The levels of CRP, ESR, plasma fibrinogen and D-Dimer returned to preoperative levels of 5.23 mg/L (range, 1.01-21.70 mg/L), 19.00 mm/h (range, 6.00-60.00 mm/h), 3.38g/L (range, 1.71-5.10 g/L) and 2.33 mm/h (range, 0.19-6.87 mg/L) at T4 point, and there was no significant difference compared with T0 point (all P 0.05).The study demonstrated the normal trajectory of CRP, ESR, plasma fibrinogen and D-Dimer at five time points in patients who underwent two-stage exchange for PJI. Thus, the results have the possibility of providing signs of infection after the patient receives two-stage exchange arthroplasty for PJI, which can benefit from early treatment.