This prospective observational diagnostic study aims to improve the accuracy and timeliness of diagnosing chronic periprosthetic joint infection (PJI). By systematically integrating clinical history, serological markers, synovial fluid analysis, microbiological cultures, next-generation sequencing (NGS), histopathology, minimally invasive arthroscopic sampling, open surgical sampling, sonication, and nuclear imaging, the study evaluates which diagnostic factors and combinations thereof most reliably identify the presence, extent, location, and causative microorganism(s) of PJI. The ultimate objective is to provide evidence-based recommendations to refine and optimize the current unified PJI diagnostic definition.