BACKGROUND: Tranexamic acid (TXA) has long been used to reduce blood loss associated with total knee arthroplasty (TKA). Debate remains over the best administration route with limited data comparing regimes including, to date, no studies investigating the equivalence of oral TXA and a combined topical/intravenous (IV) regime. Therefore, the aim of this study was to compare the efficacy and safety of oral TXA to combined topical/IV/oral TXA. WORKING HYPOTHESIS: We postulated that oral TXA would offer the same efficacy and safety as combined topical/IV/oral regime. We asked: (1) Would blood loss and haemoglobin change be affected? (2) Would complication rates increase? PATIENTS AND METHODS: Patients were randomised into either the study group (oral TXA regimen) or the control group (combined topical/IV/oral TXA). Both groups were administered three doses of TXA and received the same post-operative venous thromboembolism prophylaxis. Efficacy outcomes including blood loss and haemoglobin (Hb) change were investigated, together with safety outcomes of incidence of deep vein thrombosis and adverse events. RESULTS: The study (n=25) and control (n=28) group were comparable at baseline (eg pre-op haemoglobin). No significant difference was found between the study and control group in terms of Hb change (32.9±8.9 vs. 31.8±10.4, p=0.687) or blood loss (measured 640.0±291.1 vs. 538.3±270.2, p=0.173 and total 1211.5±336.0 vs. 1092.9±341.4, p=0.214). No cases of DVT were reported for either group and no statistical differences were found in the incidence of adverse events (nausea, hypotension, constipation) between groups. DISCUSSION: This study has shown for the first time that an oral TXA regimen is non-inferior to a topical/IV/oral regimen in TKA in efficacy and safety. Utilising oral TXA in place of a combined topical/IV/oral regime can significantly reduce costs without compromising patient outcomes. LEVEL OF EVIDENCE: II, Randomised controlled trial.