We sought to evaluate the safety and efficacy of topical administration of tranexamic acid (TXA) in high-risk patients undergoing posterior lumbar interbody fusion (PLIF) surgery. In this single-center, retrospective cohort study, a total of 120 patients with lumbar degenerative disease who had a previous history of cardiovascular or cerebrovascular embolism and who underwent single-level PLIF surgery between December 2018 and December 2019 were included and allocated to 2 groups according to whether they had been administered TXA. In the TXA group (n= 60), the wound surface was topically soaked with TXA (1 g in 100 mL of saline solution) for 5 minutes before wound closure. In the control group (n= 60), the wound surface was topically soaked with the same volume of normal saline. SPSS software, version 26.0, was employed to analyze demographics including surgical traits, blood loss, drainage, length of hospital stays (LOS), blood biochemical indices, prethrombotic state molecular markers, coagulation function, and adverse events. Total blood loss, visible blood loss, postoperative drainage, removal time of drainage tube, and LOS were significantly lower in the TXA group than in the control group. However, there was no significant difference between the 2 groups in hidden blood loss, hepatorenal function, coagulation function, prethrombotic state molecular markers, transfusion rate, or complications during the perioperative period. In single-level PLIF surgery, topical administration of TXA could significantly reduce total blood loss, visible blood loss, postoperative drainage, removal time of drainage tube, and LOS without increasing the risk of thromboembolic events in high-risk patients with prior histories of thrombosis.