Background and objective: Cardiopulmonary bypass is known to induce postoperative coagulopathy including fibrinolysis. We have evaluated the effect of the topical use of tranexamic acid in the pericardial cavity on postoperative bleeding following open heart surgery. Methods: One hundred patients, scheduled for elective open heart surgery, were included in this double-blind, prospective, randomized, controlled study. They were allocated to a treatment group (Group I), or placebo group (Group II). Patients with coagulopathies, renal failure, re-do surgery, or recent anti-platelet treatment were excluded. In Group I, tranexamic acid (2 g in 100 mL of saline solution) was poured into the pericardial cavity before sternal closure. Placebo patients received 100 mL of saline. Postoperative blood loss, need for transfusion of blood products and the rate of re-sternotomy for bleeding were documented. Results: During the first postoperative 24 h, cumulative blood loss was significantly higher in Group II compared to Group I (1208 ± 121 mL vs. 733 ± 93 mL, respectively) (P < 0.001). More blood transfusions were administered to Group II patients (4.54 ± 1.4 units) as compared to Group I patients (2.64 ± 1.5 units) (P < 0.01). Conclusion: Topical application of tranexamic acid in patients undergoing primary open heart surgery led to a significant reduction of both postoperative mediastinal bleeding, and rate of re-exploration for haemostasis.