Thromboembolic events in preterm infants constitute a serious problem in neonatal intensive care. In most cases, treatment with low-molecular-weight heparin offers a sufficient therapy of thrombotic events. We report the case of a severely sick male preterm infant with a heterozygous factor V Leiden mutation and protein C deficiency. The infant developed multiple thromboses despite adequate anticoagulation with enoxaparin and was in a life-threatening situation. Treatment with hirudin prevented the occurrence of new thromboses without causing bleeding complications. After 2 weeks hirudin was discontinued and low-molecular-weight heparin therapy was started again. A successive recanalization of the vast majority of affected vessels was observed within the following 6 months. Despite some minor neurologic sequelae and a slight delay in neuro-motor development, the 2.5-year-old boy is in a healthy condition. This case demonstrates that hirudin can be an effective alternative anticoagulant in neonates and infants refractory to heparin treatment. Efficacy and safety issues of hirudin treatment, however, need to be evaluated in randomized trials.