Tranexamic acid (TXA) decreases blood loss, perioperative transfusion rates, and cost in total hip and total knee arthroplasty. In a previous study, topical TXA decreased both perioperative blood loss and transfusions in patients undergoing resection of aggressive bone tumors and endoprosthetic reconstruction. The purpose of this study was to explore the cost effectiveness of TXA in patients undergoing resection of an aggressive bone tumor and endoprosthetic reconstruction, assessing transfusion cost, TXA administration cost, postoperative hospitalization cost, posthospital disposition, and 30-day readmissions. This study included 126 patients who underwent resection of an aggressive bone tumor and endoprosthetic resection at a single academic medical center; 61 patients in the TXA cohort and 65 patients in the non-TXA cohort. The cost of 1 unit of packed red blood cells, not including administration or complications, was estimated at our institution. The cost of hospitalization was estimated for lodging and basic care. The cost of TXA was $55 per patient. Patients were followed up for 30 days to identify hospital readmissions. Patients in the TXA cohort experienced a TXA and blood transfusion cost reduction of $155.88 per patient (P = 0.007). Proximal femur replacement patients experienced a $282.05 transfusion cost reduction (P = 0.008), whereas distal femur replacement patients only experienced a transfusion cost reduction of $32.64 (P = 0.43). An average hospital admission cost reduction of $5,072.23 per patient (P < 0.001) was associated with TXA use. Proximal femur replacement patients who received TXA experienced a hospital cost reduction of $5,728.38 (P < 0.001), whereas distal femur replacement patients experienced a reduction of $3,724.90 (P = 0.01). No differences between the cohorts were identified in discharge to home (P = 0.37) or readmissions (P = 0.77). TXA administration is cost effective in patients undergoing resection of an aggressive bone tumor and endoprosthetic reconstruction through reducing both perioperative transfusion rates and postoperative hospitalization. III-Retrospective Cohort Study.