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FDG positron emission tomography (PET) has been presented as a highly accurate technique (n = 51; accuracy 96%, no false-positive results) for diagnosing chronic osteomyelitis. The authors report a case of high FDG uptake in aseptic loosening of a knee prosthesis. The FDG uptake mechanism in infection is related to increased tracer accumulation in activated macrophages, leukocytes, and fibroblasts. Macrophages and fibroblasts also play a role in aseptic loosening. This may be reflected in an elevated FDG uptake. Although promising, FDG PET probably will not be able to distinguish infection from inflammation. Further investigation is needed to determine its value in loosened prostheses.