Abstract: It has been shown that in patients undergoing primary minor Coronary Artery Bypass Graft surgery (CABG), epsilon-aminocaproic acid (epsilon-ACA) produces a reduction in chest tube drainage and this effect was similar whether the drug is given prior to incision or following anticoagulation. The aim of this study was to investigate the efficacy of epsilon-ACA and its timing in reducing blood loss in major CABG. In a randomized double-blind study, 60 adult patients undergoing primary CABG requiring equal or more than 4 grafts with extracorporeal circulation were allocated to receive epsilon-ACA either prior to skin incision (bolus 150 mg kg-1, followed by an infusion at 15 mg kg-1 h-1), either prior to skin incision or after heparin, or placebo. All infusions were terminated at the end of cardiopulmonary bypass. Postoperative chest tube drainages (at 6, 12 h and at chest tube removal) were compared. The control group had significantly greater chest tube drainage than either of the two epsilon-ACA groups, at 6 h and chest tube removal times (p<0.05). Also there was a significant difference in postoperative chest tube drainages pattern between control and either of the two epsilon-ACA groups (p<0.05) but not between two epsilon-ACA groups. Epsilon-ACA effectively reduces blood loss through chest tubes in patients undergoing major CABG and its administration timing has no effects. Considering comparable hemostatic efficacy, it is recommended administering epsilon-ACA next to anticoagulation.