(1) Aim: To evaluate the failure reason and surface modifications of a retrieved knee prosthesis; (2) Methods: Rapid confocal Raman spectroscopy screening was applied on the surface of a retrieved knee prosthesis (both titanium and UHMWPE (Ultra-high-molecular-weight polyethylene) component) in order to determine predominate implant damage, along with the chemical composition of synovial fluid accumulated in the stem of the tibial component during the implantation period. Correlations between the medical records of the patient (clinical and radiographic information) and spectroscopic results are pointed out, the parameters being interpreted in the context of proper functioning and life span of knee prosthesis; (3) Results: The metallic tibial component does not show any modification during the implantation period, as demonstrated by the well preserved titanium component with signature of anatase phase detected in retrieved component, compared to unused piece. The spectral features of polymeric component (ultrahigh molecular weight polyethylene, UHMWPE) revealed structural modification in crystallinity and amorphous phase accompanied by insignificant level of oxidation (OI < 1). Scratching, pitting and persistent organic spots as a result of mechanical and chemical deterioration were noticed on the surface of retrieved insert. Acrylic cement deterioration was also noticed. Synovial fluid collected from the stem of the tibial component demonstrated a lipidomic profile; (4) Conclusions: Combining the clinical evidences with confocal Raman spectroscopy allowed a rapid screening with high sensitivity and nondestructive measurements in the case of failure in TKA (total knee arthroplasty). The third body wear and lipidomic profile of synovial fluid are cumulative factors of failure in this case, resulting in an osteolysis that finally leads to an aseptic loosening.