Background: Because there is no single gold-standard method for the diagnosis of periprosthetic joint infection (PJI), the combination of valuable methods to evaluate infection seems to achieve a better diagnostic result. The objective of the present study was to evaluate the diagnostic value of serum interleukin (IL)-6 and C-reactive protein (CRP) for the diagnosis of PJI.Methods: PubMed, Embase, and the Web of Science databases were searched for articles describing PJI diagnosis using serum IL-6 and CRP published between January 1990 and December 2019.Results: Eight studies were included in the meta-analysis. The pooled sensitivity was 0.79 (95% confidence interval [CI]: 0.73 to 0.83) for the combined method (serum IL-6 and CRP), 0.87 (95% CI: 0.82 to 0.91) for IL-6 and 0.83 (95% CI: 0.78 to 0.87) for CRP . The pooled specificity was 0.92 (95% CI: 0.89 to 0.95) for the combined method, 0.85 (95% CI: 0.81 to 0.88) for IL-6, and 0.83 (95% CI: 0.79 to 0.87) for CRP. The combined method had the highest value for the area under the curve (0.9688), followed by IL-6 (0.9259) and CRP (0.9139). Subgroup analyses showed that restricting antibiotic treatment before sample collection may improve specificity.Conclusion: The combination of serum IL-6 and CRP was a reliable tool for the diagnosis of PJI, and it had a better diagnostic accuracy than testing with a single marker, especially when samples were collected without antibiotic therapy. Additional research is needed.