INTRODUCTION: Children undergoing complex cranial vault reconstruction (CCVR) for craniosynostosis experience high rates of bleeding and transfusion, increasing risk for perioperative complications. ε-Aminocaproic acid (EACA) and tranexamic acid (TXA) are antifibrinolytic agents that have been shown to reduce intraoperative hemorrhage and transfusion requirements during CCVR. However, the relative efficacy of these two agents has not yet been evaluated. The aim of this study was to compare perioperative blood loss and transfusion rates in children receiving EACA vs. TXA. METHODS: All patients who underwent CCVR from September 2015 to December 2019 at a single center were retrospectively evaluated. Primary outcome measures included intraoperative estimated blood loss, postoperative drain output, transfusion volumes, and calculated blood loss. Secondary outcome measures included hematologic and coagulation parameters. RESULTS: 95 patients were included, with 47 patients in the EACA cohort and 48 patients in the TXA cohort. There were no significant differences in demographics, surgical outcomes, blood loss, transfusion requirement, or perioperative hematologic and coagulation laboratory values between the two cohorts. Adverse events were similar between the groups, but did include two seizure events and two thromboembolic events related to vascular access devices. DISCUSSION: We found no significant difference in blood loss, transfusion requirements, hematologic parameters, or outcomes between pediatric CCVR patients who received EACA vs. TXA. Further research is needed to define optimal antifibrinolytic dosing and duration of therapy. While standard laboratory parameters were similar between groups, future studies investigating coagulation-based and inflammatory assays may be useful in defining surgical-induced coagulopathy.