A multicenter prospective study was conducted to determine whether epoetin alfa could be used to lower transfusion requirements after two-stage exchange arthroplasty for infection. Forty-one consecutive patients undergoing successful two-stage exchange arthroplasty for an infected total knee arthroplasty were enrolled in a prospective study. Epoetin alfa (40,000 units) was administered subcutaneously after prosthesis resection and antibiotic spacer placement. Although there was no difference in the hemoglobin levels before resection arthroplasty or on postoperative Day 3 between the study group and the control group, hemoglobin levels before reimplantation were higher in the patients who received epoetin alfa (12.4 mg/dL; range, 9.3-15.1 mg/dL) compared with the control group (11.3 mg/dL; range, 8.1-14.4 mg/dL). Average increase in hemoglobin level in the interval between stages was higher in the treatment group (3.2 mg/dL; range, -0.7-6.8 mg/dL) than the control group (1.7 mg/dL; range, -1.9-6 mg/dL). The transfusion rate decreased from 83% of patients in the control group to 34% in the study group during reimplantation. In addition, overall incidence of transfusion for either stage improved from 89% in the control group to 44% in the patients treated with epoetin alfa. Perioperative epoetin alfa statistically increased the hemoglobin levels and decreased transfusion rates for patients undergoing two-stage revision for infected total knee arthroplasty.