One hundred five consecutive painful knee arthroplasties were evaluated by a single surgeon for the presence of infection using a uniform protocol that included an erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), perioperative aspiration with synovial fluid white blood cell (WBC) count and differential, intraoperative frozen section analysis, and culture. A synovial fluid WBC count of greater than 3000 was the most precise test with a sensitivity of 100%, specificity of 98%, and accuracy of 99%. The preoperative use of an ESR and CRP proved to be an excellent screening modality with only one infection identified with both values being normal. A rational approach to perioperative testing for sepsis includes a screening ESR and CRP, and if elevated, aspiration with synovial fluid WBC count or an intraoperative frozen section.