Thrombolytic therapy of a systemic pulmonary fistula is a rare method of treatment in newborns with thrombosed systemic-pulmonary shunt. We report the case of a newborn girl with a complex congenital heart defect. On the ninth day of life a modified right Blalock-Taussig shunt was performed. The ductus arteriosus was not ligated. Six days later the baby developed severe hypoxemia. The results of echocardiography and cardiac catheterization showed a total thrombosis of the fistula and complete absence of flow throughout the shunt. After insertion of an arterial catheter into the proximal end of the shunt we started fibrinolytic treatment with recombinant tissue plasminogen activator (r-TPA) in continuous infusion. After 14 hours of treatment we confirmed by angiography complete clot dissolution. The baby left the hospital in good condition when she was 23 days old. In the follow-up (4th month of life) the shunt is still permeable. Thrombolytic therapy with r-TPA locally applied in case of acute thrombosis of a systemic-pulmonary shunt appears to be a good therapeutic option avoiding the risks of a new surgical procedure.