Objective To explore the meaning of serum D-Dimer in the diagnosis of Prosthetic Joint Infection. Methods In a retrospective study, 80 patients presented with osteoarthritis, PJI, aseptic loosening after joint arthroplasy were divided into three groups according to the type of operation they received. Group A: 33 patients treated with primary arthroplasty; Group B: 24 PJI patients treated with resection arthroplasty and spacer insertion surgery; Group C: 23 aseptic loosening patients treated with revision arthroplasty. Record gender, age, serum CRP, ESR and D-Dimer level preoperatively in patients from the three different groups. Results There are no statistically significant differences when compared general data such as gender and age in patients from the three different groups. Serum CRP and ESR level in Group B are much higher than Group A and C. Serum D-Dimer level in Group B are much higher than Group A, but similar with Group C. There are no statistically significant differences when compared with sensitivity and specificity of CRP, ESR, D-Dimer in the diagnosis of PJI among patients from the three different groups when D-Dimer>0.85μg/L was set as the optimal threshold value for the diagnosis of PJI. However, when D-Dimer>0.5μg/L was set as the optimal threshold value for the diagnosis of PJI, the sensitivity of D-Dimer in diagnosis of PJI was similar with CRP and ESR, whereas, the specificity is much lower than CRP and ESR. Conclusion Serum D-Dimer does not perform better than CRP and ESR in PJI diagnosis.