Controversies exist over the currently recommended guidelines for the use of low-molecular-weight heparin (LMWH) in neonates. We retrospectively studied 30 neonates treated with LMWH and found a poor therapeutic response to recommended doses as measured by anti-Xa levels. Sixty percent of the study participants required their doses to be increased because of subtherapeutic anti-Xa levels during the initial course of their treatment. The mean starting enoxaparin dose was 1.53 ± 0.38 mg/kg. The mean enoxaparin dose, once therapeutic anti-Xa levels had been achieved, was 1.86 ± 0.50 mg/kg. Preterm and term infants required doses of 2.06 ± 0.61 mg/kg and 1.67 ± 0.26 mg/kg, respectively, to achieve therapeutic anti-Xa levels. In summary, our results suggest that higher initial doses are required to achieve therapeutic anticoagulation in neonates.