Total knee arthroplasty is successful in the treatment of degenerative, arthritic or injured joints. But the most important long term complication seems to be aseptic loosening. An inflammatory process at the bone/cement or bone/prosthesis interface leads to a severe osteolysis. Although early diagnosis is very important the standard techniques often fail. [(18)F]Fluoride ion positron emission tomography (F-PET) is an appropriate tracer paired with a modern method for the evaluation of increased bone metabolism at the bone/prosthesis interface. In this preliminary study we describe for the first time the value of F-PET in the early diagnosis of aseptic loosening. We studied 14 painful knee arthoplasties. In 6 cases the definite diagnosis was determined by surgical procedure, for 8 cases a long clinical follow-up of the least 6 months after the onset of symptoms led to the diagnosis. The F-PET scans were obtained by with an ECAT EXACT HR+ scanner with and without attenuation correction in the two-and three-dimensional mode. An intermediate or high uptake along the bone/prosthesis or bone/cement interface including either the tibial stem or the half of the femoral component was suspected to be aseptic loose. The result were compared with plain radiographs. We found a sensitivity of 100%, a specificity of 56% and an accuracy of 71%. No false negative results were detected, in 4 patients one component as false positive. The sensitivity, specificity and accuracy for the plain radiograph of the same patients were 43%, 86% and 64%, respectively. In conclusion PET seems to be a promising new method in the early diagnosis of painful TKA because of its excellent spatial solution. In combination with the bone seeking tracer [(18) F]fluoride, PET allows the detection of aseptic loosening and the differentiation to the simple synovitis. Our preliminary results suggest that F-PET could be a useful tool although we examined a small group of patients.