Objective  To observe the effects of online closed two-way blood re-infusion at the end of hemodiafiltration therapy.  Methods   A total of 43 patients who received regular hemodialysis treatment in the Blood Purification Center of South Renji Hospital affiliated to Shanghai Jiaotong University School of Medicine from May 1 to August 1 2020 were selected. Three methods of open blood return, closed two-way blood return and online closed two-way blood return were used respectively. Every patient received 8 times of blood return, and the blood return time of the three methods was compared.  Results  The shortest time of blood return was online closed two-way blood return (197.19±3.55)s, followed by open two-way blood return (198.85±4.41)s, and closed two-way blood return (213.74±7.99)s; the difference was statistically significant (F=2.898, P=0.009).  Conclusion   The online closed two-way blood return method is simple and can shorten the blood return time. As the main liquid for blood return, the replacement fluid is reduced to save medical expenses. This method is worthy of clinical promotion.