Aim: The purpose of this study was to optimize the dosing schedule of recombinant human erythropoietin (rhEPO) for perioperative autologous blood donation in patients undergoing total knee arthroplasty (TKA). Method: TKA patients receiving different dosing schedules of rhEPO were randomly divided into three groups. Group A patients were given 10,000 IU of subcutaneous rhEPO (1 ml) daily from preoperative day 5 to postoperative day 3 (9 doses); Group B patients were given subcutaneous normal saline daily from preoperative day 5 to day 3 and then subcutaneous rhEPO daily until postoperative day 3 (6 doses in total); Group C patients were given subcutaneous normal saline daily from preoperative day 5 to the day before surgery and then subcutaneous rhEPO daily from the surgery day to postoperative day 3 (4 doses). Results: A total of 180 TKA patients were included. On postoperative day 1 and 3, group A showed significantly higher Hb levels than group B and group C. The calculated blood loss was significantly greater in groups B and C than in group A on the day after surgery. Regarding total blood loss, groups B and C lost significantly more blood than group A. No case of allogeneic transfusion occurred during the trial in any of the three groups. Conclusions: A small dose of daily rhEPO from preoperative day 5 to postoperative day 3 could significantly increase perioperative autologous blood donation efficacy and slow the decline in postoperative Hb levels in TKA patients without causing extra complications.