The orthopedic community continues to struggle for accurate diagnosis of periprosthetic joint infection (PJI) as it is a devastating complication after total joint arthroplasty. There is no universally accepted diagnostic test that is absolute or reliable for detection of PJI. Recent research has raised doubt regarding the utility of various inflammatory markers in diagnosis. The aim of study is to evaluate the diagnostic value of interleukin- 6 (IL-6) and other inflammatory markers; C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and white blood cell count (WBC) in the diagnosis of PJI. The study group included 40 patients (21 males, 19 females) admitted for surgical intervention after knee or hip arthroplasties. Patients were subjected to careful history taking, thorough clinical examination and preoperative laboratory investigations including serum IL-6, CRP, WBC and ESR. Peri-implant tissue specimens were subjected to microbiological culture and histopathological examination. The mean age of the studied patients was (58.4 year) (range, 38-72 years). Intraoperative cultures and histopathological examination revealed that 11 patients had been infected (PJI), and 29 patients were aseptic failure of the prosthesis. Four presumed markers of infection were tested preoperatively: ESR; CRP; WBC; and IL-6. Results showed that ESR (p = 0.0001), CRP (P=0.004), WBC (0.0001), and IL-6 (P = 0.0001) were significantly higher in patients with septic revision arthroplasty than those with aseptic failure of the prosthesis both among patients with hip arthroplasty and those with knee arthroplasty. Serum IL-6 (> 10.4 pg/ml) reportedly had a sensitivity (100%), a specificity (90.9%), a PPV (79%), a NPV (100%), and accuracy (92.5%). In conclusions, the present study demonstrated that IL-6 was the most accurate laboratory marker for diagnosing PJI when compared to ESR, CRP, and WBC. We also found that IL-6 above 10.4 pg/ml and CRP level above 18 mg/L identified all patients with PJI and the combination of CRP+ IL-6 was an excellent screening test to identify all such patients (sensitivity 100%, NPV 100%).