Objective: To investigate the incidence of postoperative generalized seizures in patients undergoing aortic valve replacement (AVR) under extracorporeal circulation, who received either high-dose tranexamic acid (TXA) or epsilon aminocaproic acid (EACA) as an antifibrinolytic agent. Methods: This retrospective analysis comprised 682 consecutive patients undergoing AVR with or without simultaneous coronary artery bypass surgery. Patients operated on before March 2008 were treated intra-operatively with TXA (100 mg kg⁻¹; n = 341), patients operated on after March 2008 received EACA (50 mg kg⁻¹ loading dose, followed by 25 mg kg⁻¹ h⁻¹, and an additional 5 g in the extracorporeal circuit; n = 341). Results: Clinically diagnosed generalized seizures were observed within the first 24 h postoperatively, more frequently in patients receiving TXA compared with EACA (6.4% vs 0.6%, p ≪ 0.001, difference = 5.8%, 95% confidence interval 3.1–8.5%). Besides the antifibrinolytic agent, three other variables differed significantly between patients with and without postoperative seizures: age (mean (SD), 77.0 (5.9) years vs 73.2 (9.0) years, p = 0.039), preoperative creatinine clearance (55.4 (16.5) ml min⁻¹ vs 72.6 (28.5) ml min⁻¹, p = 0.002), and administration of recombinant activated factor VIIa (3 out of 24 patients (12.5%) vs 8 out of 658 patients (1.2%), p = 0.005). Logistic regression analysis demonstrated a significant impact of the antifibrinolytic drug, creatinine clearance, and the application of recombinant activated factor VIIa on the occurrence of generalized seizures. Conclusions: Our results indicate that high-dose TXA is associated with an increased incidence of postoperative generalized seizures in patients undergoing AVR compared with EACA, especially when suffering from renal impairment. A possible association between recombinant activated factor VIIa and the occurrence of postoperative seizures needs further investigation.