The purpose of this study was to investigate the comparative diagnostic strength of C-reactive protein (CRP) values in synovial fluid and serum in patients with presumed periprosthetic joint infection. We collected 44 synovial fluid samples and 24 serum samples from 43 patients. Patients were judged to be uninfected or infected based on standardized criteria. Synovial and serum samples were obtained simultaneously. We determined the diagnostic strength of our assay by using receiver operating characteristic curve analysis, calculated the cutoff value and calculated the difference in diagnostic strength for periprosthetic joint infection between synovial fluid and blood serum analysis. The area under the curve was 0.977 for intra-articular CRP analysis and 0.979 for serum CRP analysis. The cutoff points for intra-articular CRP analysis where 1.8 mg/L and 2.8 mg/L. Both tests showed a very high diagnostic strength; the difference in diagnostic strength between synovial fluid and blood serum analysis was not significant (p = 0.66).