Tranexamic acid (TXA) is an antifibrinolytic drug that reduces blood loss in patients that undergo Total knee arthroplasty (TKA). Few studies compare its effect on conventional instrumentation (CI) versus patient-specific instrumentation (PSI). The main objective of this study was to understand analytically how TXA usage in both instrumentations influenced blood loss in TKA differently and see if the differences seen could be explained by the patient's body mass index (BMI) and gender. This nonrandomized retrospective study sample consisted of 688 TKA procedures performed on patients who had symptomatic arthrosis resistant to conservative treatment. Descriptive analysis was used to evaluate blood loss using hemoglobin (Hb) mean values and mean variation (%). The Classification and Regression Tree (CRT) method was applied to understand how the independent variables affected the dependent variable. Comparing patients submitted to the same instrumentation, where some received TXA and others did not, patients that received TXA had lower blood loss. Comparing patients who underwent TKA with different instrumentations and without the use of TXA, it was found that patients who underwent TKA with PSI had lower blood loss than those who underwent TKA with CI. However, when these same instruments were compared again, but associated with the use of TXA, the opposite was true with patients undergoing TKA with PSI showing greater blood loss than patients undergoing TKA with CI. TXA usage in TKA is significantly beneficial in minimizing blood loss and regardless of instrumentation. When using TXA, the lowest blood loss was obtained in patients with higher BMI and submitted to TKA with CI. This is most likely explained by the synergistic antifibrotic effect of TXA with adipokines, such as plasminogen activator inhibitor-1 (PAI-1), found in the femoral bone marrow which is perforated using CI. If, however, TXA wasn't used, the lowest blood loss was obtained in patients submitted to TKA with PSI.