Aim: In this study we aimed to compare the efficacy and safety of enoxaparin with unfractioned heparin (UFH) as anticoagulant for continuous venovenous hemodialysis (CVVHD). Methods: An open-label randomized controlled trial was carried out in an intensive care unit (ICU) where 40 patients with acute renal failure (ARF) who needed continuous renal replacement therapy were randomized to receive UFH (n = 21) or enoxaparin (n = 19). Coagulation parameters were evaluated, and antithrombotic activity of UFH was measured by activated partial thromboplastin time (aPTT) and for enoxaparin by anti-factor Xa activity. Primary outcomes were thrombosis of the extracorporeal circuit and bleeding, classified as major or minor. Results: Minor bleeding episodes were observed only in patients anticoagulated with enoxaparin (26 vs. 0%, p = 0.018). Comparing patients with or without bleeding after 24 hours of therapy, the level of anticoagulation tended to be higher (anti-factor Xa: 1.62 vs. 1.13 IU mL, p = 0.09) and the platelet count to be lower 107 ± 53 vs. 229 ± 84 (×103 μL), p = 0.09 in patients who bled, but without statistical difference. Filter life span of enoxaparin and UFH groups was similar (43 ± 15 vs. 52 ± 18 hr, p = 0.10), as well as the proportion of circuit clotting. Conclusion: Weight-unadjusted enoxaparin in patients with ARF in CVVHD was associated with an increased rate of bleeding, a finding that addresses the need to adjust drug dose and to monitor anti-factor Xa activity during dialysis. No benefit to prolong dialysis circuit survival was found with enoxaparin. In patients who do not present contraindication for systemic anticoagulation, UFH remains an effective and low-cost option.