Infection of a knee prosthesis leads to specific problems in relation to the function of the knee joint. Making an accurate and early diagnosis is the first step in effectively managing patients with periprosthetic joint infection. At the present time, the diagnosis remains dependant on clinical judgment and reliance on standard clinical tests, including serologic tests, analysis of the aspirated joint fluid and interpretation of the intra-operative tissue and fluid test results. The screening test results that may suggest the possibility of infection include elevation of the erythrocyte sedimentation rate and/or the serum C-reactive protein level at more than three months after an arthroplasty. Cultures of the aspirated joint fluid can be especially helpful for patients who have symptoms suggestive of infection. The joint fluid cell counts may also be helpful, but Gram staining of the joint fluid has poor sensitivity and specificity. Intra-operative culture should not be used as a gold standard for periprosthetic infection owing to the high percentages of false-negative and false-positive cases. The criteria for diagnosing infection on the basis of frozen sections of implant membranes have not yet been standardized, but in many laboratories, more than five neutrophils per high-power field in five or more fields have been found to be suggestive of infection. Combined with clinical judgment, the total white cell count and percentage of neutrophils in the synovial fluid more accurately reflects periprosthetic joint infection. When this is combined with hematologic exams, infection can be safely excluded or confirmed.