The differential diagnosis of pain after total knee arthroplasty includes infection. Effective screening tools should have high sensitivity and are cost-effective. We evaluated 296 patients who underwent total knee revision at our institution. One hundred sixteen patients (39%) were classified as infected and 180 patients (61%) were considered noninfected. The mean erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) of the infected patients were 85 mm/h and 110 mg/L, respectively. The mean ESR and CRP of the noninfected patients were 22 mm/h and 7 mg/L, respectively. Five patients (4%) in the infected group had both normal ESR and CRP. Infection was suspected in all 5 patients, and an organism was cultured in 4 of the 5 cases. Erythrocyte sedimentation rate and CRP, when used in combination, serve as a useful screening tool in patients with a painful total knee arthroplasty.