A 2300-g pre-term neonate with severe hyaline membrane disease experienced right forearm and hand ischemia following a brachial arterial line insertion. Limb salvage was achieved through combined microsurgical exploration and thrombectomy of the brachial and radial arteries, with postoperative regional infusion of tissue plasminogen activator (TPA) through the distal radial artery for 48 hr, to dissolve a thrombus within the small vessels of the hand. This report advocates combined surgical and regional thrombolytic therapy with tissue plasminogen activator as management for neonatal arterial thrombosis and limb ischemia.