Background: Plastic bronchitis (PB) is a rare disease that is characterized by formation of rubber-like tracheobronchial casts that occlude the airway, occurring secondary to several conditions, most commonly as a complication of single-ventricle palliative cardiac surgery. Inhaled tissue plasminogen activator (t-PA) was reported to be effective in treating PB. Aim of the work: To show the outcome and safety of a long course of inhaled tissue plasminogen activator in the management of plastic bronchitis. Methodology: this was a case report, we report the case of a teen with PB treated with a prolonged course of t-PA with no adverse effects. Results: we reported the case of an 11-year-old boy with trisomy 21 who had a Fontan procedure for his complex congenital heart disease, complicated by PB that was treated with a prolonged course of t-PA. Our patient was an 11-year-old boy with trisomy 21 who was diagnosed with an unbalanced AV canal defect with a small right ventricle and bilateralsuperior vena cava. His surgical cardiac course consisted of a pulmonary artery banding at 2 months of age and bilateral bidirectional Glenn with tightening of the pulmonary artery banding at 24 months of age. He had pulmonary artery debanding and ligation of both right and left Glenn shunts at the age of 6 years. Since the age of 3 years, he was admitted many times to the hospital with various diagnoses, including bronchial asthma, bronchopneumonia and pulmonary hypertension, all of which were treated accordingly. He was admitted at the age of 9 years with a history of fever and cough productive of plastic-like material that took the form of the bronchial tree. The diagnosis of PB was confirmed. Subsequently, he was admitted frequently with the diagnosis of PB and was treated with aggressive airway clearance including hypertonic saline, dornase alpha and t-PA. The longest t-PA duration was 82 days, which clinically proved to be effective and safe. Conclusion: PB is a rare and serious disease. The long-term use of inhaled t-PA was effective and safe.