Antifibrinolytic drugs have been used for decades primarily due to their capacity to decrease blood loss and reduce the need for allogeneic transfusion in patients undergoing cardiac or noncardiac surgery. The three main antifibrinolytic drugs are aprotinin, which was first used in Germany in the late 1950 s; aminocaproic acid, which was approved by the Food and Drug Administration in 1964; and tranexamic acid (TXA), which was made available in 1986. It is remarkable that despite widespread use of these drugs over several decades, there is still no consensus regarding their optimal dose and dosing regimen. The need to resolve this debate is becoming increasingly urgent, as the clinical use of antifibrinolytics is expected to rise due to the increasing number of complex surgeries being performed and the expanded use beyond cardiac surgery. Specifically, the use of TXA in noncardiac surgery is likely to increase following the recent demonstration that this drug reduces mortality in trauma patients. 1 Moreover, all three agents are associated with significant adverse effects. Tranexamic acid has been reported to be associated with an increased incidence of postoperative seizures, 2 whereas aprotinin has been associated with increases in renal dysfunction and mortality. 3 Thus, serious questions remain about the relative efficacy and safety of antifibrinolytic drugs. In this issue of the Journal, Manji et al. 4 address a pertinent safety concern related to the use of antifibrinolytic drugs: the incidence of postoperative seizures in patients who have undergone cardiac surgery. The aim of their study was to identify risk factors for seizures following cardiac surgery. Manji et al. performed a retrospective analysis of consecutive patients who underwent cardiac surgery between April 2003 and December 2009. Despite the limitations of retrospective analyses (including, in this instance, missing data for 5-10% of patients and lack of specific monitoring for seizures), the authors identified seven important factors that were significantly associated with seizures: exposure to TXA, APACHE II score [20, preoperative cardiac arrest, preoperative neurological disease, open chamber surgery, cardiopulmonary bypass time [150 min, and previous cardiac surgery. All of these risk factors, other than TXA exposure, indicate that the incidence of seizures is strongly associated with the ‘‘sickness’’of the patient. The authors also found a relationship between changes in TXA dosing and incidence of seizures over time. More specifically, patients whose estimated TXA dose was between 1.4 and 1.7 g (during the period 2003–2006) had a seizure rate of 0.0-0.3%, whereas those whose TXA dose was between 5.1 and 5.8 g (over the period 2007–2009) had a seizure rate of 1.2-1.8%. Reduction of the mean TXA dose to 3.1 g (in 2010) was associated with a concurrent decrease in