Complete inferior vena cava thrombosis (IVC) in neonates is uncommon, but may cause significant morbidity. A 13-day-old neonate suffered IVC thrombosis secondary to antithrombin III deficiency, possibly contributed to by a mutation in the methyl tetrahydrofolate reductase gene. Catheter-directed thrombolysis (CDT) with recombinant tissue plasminogen activator (rt-PA, Alteplase) was used successfully to treat extensive venous thrombosis in this neonate without complications. We also review the literature on CDT for treatment of IVC thrombosis in critically ill neonates and infants.