Background: Identify incidence, etiology, and predictors of extubation failure in neonates and infants who underwent Norwood operation with either a modified Blalock-Taussig shunt (mBTS) or a Sano shunt at a single tertiary care, academic children's hospital. Methods: Extubation failure for our study was defined as reintubation within 96 hours after extubation. We collected demographics, preoperative, intraoperative, postoperative, and peri-extubation data in a retrospective, observational format in patients who underwent Norwood operation with either a modified Blalock-Taussig shunt (mBTS) or a Sano shunt between January 2005 and March 2011. Clinical outcomes evaluated included the success or failure of extubation, cardiac intensive care unit (CICU) length of stay (LOS), hospital LOS, and mortality. Descriptive, univariate, and multivariate statistics were utilized to compare groups with extubation failure and extubation success. Results: Of 64 eligible patients during the study period, extubation failure occurred in 22% (14 of 64) of the patients. Eight patients failed extubation in the first 24 hours with an extubation failure rate of 12%. The median age of patients was 18 days (range 13.75 days to 22 days) and median weight of patients was 3.37 kg (range 3.11 kg to 3.86 kg). Twelve patients received a mBTS while 52 patients received a Sano shunt. All extubation failures occurred in patients receiving a Sano shunt. The most common risk factors for failed extubation were lung disease in 29% (4 of 14), cardiac dysfunction in 21% (3 of 14), diaphragmatic paralysis in 14% (2 of 14), airway edema in 14% (2 of 14), vocal cord paralysis in 14% (2 of 14), and laryngotracheomalacia in 7% (1 of 14). Patients with extubation failure had longer CICU LOS and hospital LOS. Overall mortality at the time of hospital discharge was 8%. Independent predictors of extubation failure included use of nitric oxide after surgery, increased days of mechanical ventilation prior to extubation, elevated inotrope score leaving the operating room, and presence of atelectasis prior to extubation. Conclusions: Extubation failure in children after the Norwood operation is a slow and evolving process occurring as late as 96 hours after extubation and is not associated with an increase in in-hospital mortality. Causes of failed extubation are diverse. Successful weaning from positive pressure ventilation depends on adequate cardiovascular function, the presence of satisfactory ventilatory reserves, and favorable pulmonary mechanics.