600 patients scheduled for total knee arthroplasty were randomized to one of three groups: (1) traditional erythropoietin (EPO) dosing, (2) new protocol EPO dosing, or (3) placebo injection. The purpose of this study was to investigate and compare the two EPO dosing protocols with the placebo group by assessing hemoglobin levels, the requirement of postoperative transfusion, cost of hospital stay, and incidence of thromboembolic events. Results demonstrated that the new EPO dosing protocol (a single 40,000 IU EPO administration 4 weeks prior to surgery, with an optional additional dose if hemoglobin was less than 12.5 g/dl on the day of surgery) was associated with a decreased cost of hospital stay when compared to traditional EPO protocol, while still maintaining significantly better hemoglobin levels, decreased requirement for transfusion, and comparable complication rate when compared to the placebo group.