Abstract Background: Tranexamic acid (TXA) is an anti-fibrinolytic drug widely used to reduce blood loss during major operations, including total laryngectomy with neck dissection. However, there is no final consensus regarding the optimal route of ad-ministration of TXA regime whether topical, intravenous or combined. Aim of Study: The purpose of our study was to compare the efficacy of topical and intravenous (IV) regimen of TXA to control bleedingduring Total Laryngectomy with neck dis-section. Patients and Methods: This randomized controlled trial (RCTs) compared topical with intravenous TXA including pa-tients underwent total laryngectomy with neck dissection. For-ty-five patients were enrolled in this study and were divided into 3 different groups. Group (A) received IV TXA on 1mg/ kg before induction, while Group (B) received Topical TXA in the form of irrigation of 2mg/ kg on 200 ml normal saline every one hour after flap elevation for five hours, and Group (C) was the control group. Results: Total blood loss was significantly lower in Group A than (Group B and Group C) (p-value=0.004 and <0.001 respectively) and insignificantly different between Group B and Group C. Duration of operation was significantly lower in Group A than (Group B and Group C). Need for blood transfu-sion and postoperative hemoglobin levels were insignificantly different among the three groups. Conclusions: Intravenous TXA was more efficient in re-ducing blood loss than topical irrigation of TXA.