Abstract Background Oxidized regenerated cellulose (ORC) is a type of biodegradable hemostatic material, which has been widely used in the field of surgery. However, its hemostatic effect in patients undergoing total knee arthroplasty (TKA) is uncertain. Accordingly, this study investigated the effectiveness and safety of ORC in patients receiving TKA. Methods Seventy patients undergoing unilateral TKA were randomized into blank control group and ORC (2 pieces of ORC placed in the joint cavity) groups. Then, the two groups were compared for primary (perioperative blood loss [total blood loss, intraoperative blood loss, and hidden blood loss] and hemoglobin drop values) and secondary (coagulation indicators, inflammatory indicators,operation time, and complication rates) outcomes. Results The total blood loss in the ORC group was 902.32 ± 307.82 mL, which was statistically significantly lower than that in the control group (1052.25 ± 308.44 mL) (P