Abstract: Diagnostic assays and related systems, test samples and methods are described for detection of infection following implantation of a prosthetic material or device on and/or into bones and joints. A combination of at least two biomarkers is used, one specific to the pathogenic microbe and the other specific to the destruction of peri-implant tissues. The biomarkers are detectable in the peripheral blood, urine, fluid or tissue samples drawn from a peri-implant environment. They can also be detected with a blood or urine test that is highly sensitive for detecting specific structural microbial molecules and peri-implant tissue components.