Background: The oral direct thrombin inhibitor ximelagatran, and its active form, melagatran, have been tested in various clinical conditions as a promising alternative to conventional anticoagulant therapy (CAT), despite some concerns over potentially serious liver injury. Objectives: To assess its risk/benefit profile, a systematic review and meta-analysis of all randomised controlled trials (RCTs) comparing xi-/melagatran to CAT was performed. Methods: Leading medical databases were searched. The rates of major adverse events (MAE: all cause death, nonfatal myocardial infarction, nonfatal thromboembolic stroke, nonfatal pulmonary embolism), major bleeds (MB), and hepatotoxicity were compared. Out of 140 potentially relevant citations, 13 RCTs enrolling 22,639 patients were included. Indications for treatment were: 1) perioperative prophylaxis of deep vein thrombosis (DVT); 2) management of DVT; and 3) stroke prevention in atrial fibrillation. Results: Overall, the risk of MAE (OR 0.98 [0.83-1.17]) and MB (OR 1.01 [0.69-1.47]) did not differ significantly between xi-/melagatran and CAT. There was a clear trend towards an increased risk of hepatotoxicity (OR 1.74 [0.50-6.01]), with an incidence of 5.8% with xi-/melagatran versus 2.3% with CAT (p < 0.001); more specifically, the rate of hepatotoxicity was markedly augmented in the management of DVT (OR 5.16 [3.38-7.89]), for treatment durations ≥ 3 months (OR 6.73 [5.01-9.05]), and in the prevention of atrial fibrillation-related stroke (OR 8.31 [5.65-12.23]). Two fatal cases of liver injury occurred with xi-/melagatran. Conclusions: Although comparable to CAT in terms of MAE and MB, xi-/melagatran carries a prohibitive risk of hepatotoxicity that cannot be ignored. Newer long-term alternatives are urgently needed.