Objective: Tranexamic acid has been suggested to be as effective as aprotinin in reducing blood loss and transfusion requirements after cardiac surgery. Previous studies directly comparing both antifibrinolytics focus on high-risk cardiac surgery patients only or suffer from methodological problems. We wanted to compare the effectiveness of tranexamic acid versus aprotinin in reducing postoperative blood loss and transfusion requirements in the patient group representing the majority of cardiac surgery patients: low- and intermediate-risk patients. Methods: We conducted a non-sponsored, double-blind, randomised, placebo-controlled trial in which 298 patients scheduled for low- or intermediate-risk (mean logistic EuroSCORE 4.1) first-time heart surgery with use of cardiopulmonary bypass were randomised to receive either tranexamic acid, high-dose aprotinin, or placebo. All patients had preoperative normal renal function. End points of the study were monitored from the time of surgery until patient discharge. This trial was executed between June 2004 and October 2006. Results: Both antifibrinolytics significantly reduced blood loss and transfusion requirements when compared with placebo. Aprotinin was about twice as effective as tranexamic acid in reducing total postoperative blood loss (estimated median difference 155 ml, 95% confidence interval (CI) 60–260; p ≪ 0.001). Accordingly, aprotinin reduced packed red blood cell transfusions more than tranexamic acid, although the difference did not reach statistical significance. Only aprotinin significantly reduced the proportion of transfused patients when compared with placebo (mean difference −20.9%, 95% CI 7.3–33.5; p = 0.013), and only aprotinin completely abolished bleeding-related re-explorations (mean difference 6.8%, 95% CI 1.6–13.4%; p = 0.004). Neither antifibrinolytic agent increased the incidence of mortality (mean difference tranexamic acid −0.4%, 95% CI −4.6 to 4.4; p = 0.79, mean difference aprotinin −1.3%, 95% CI −6.2 to 3.5; p = 0.62) or other serious adverse events when compared with placebo. Conclusion: Aprotinin has clinically significant advantages over tranexamic acid in patients with normal renal function scheduled for low- or intermediate-risk cardiac surgery.