Serum C-reactive protein, fibrinogen, and interleukin-6 show the best performance among serum markers for diagnosing periprosthetic joint infection (PJI), but they lack sufficient accuracy to confirm or exclude infection reliably. These markers should be re-evaluated in future PJI definitions, as they are not suitable as stand-alone tests. Given their limitations and the superior diagnostic performance of synovial markers, the role of serum markers in PJI diagnosis should be reconsidered.