OBJECTIVES: To describe the epidemiology of extubation failure and identify risk factors for its occurrence in a multicenter population of neonates undergoing surgery for congenital heart disease. STUDY DESIGN: We conducted a prospective observational study of neonates =30 days of age who underwent cardiac surgery at 7 centers within the US in 2015. Extubation failure was defined as reintubation within 72 hours of the first planned extubation. Risk factors were identified with the use of multivariable logistic regression analysis and reported as OR with 95% CIs. Multivariable logistic regression analysis was conducted to examine the relationship between extubation failure and worse clinical outcome, defined as hospital length of stay in the upper 25% or operative mortality. RESULTS: We enrolled 283 neonates, of whom 35 (12%) failed their first extubation at a median time of 7.5 hours (range 1-70 hours). In a multivariable model, use of uncuffed endotracheal tubes (OR 4.6; 95% CI 1.8-11.6) and open sternotomy of 4 days or more (OR 4.8; 95% CI 1.3-17.1) were associated independently with extubation failure. Accordingly, extubation failure was determined to be an independent risk factor for worse clinical outcome (OR 5.1; 95% CI 2-13). CONCLUSIONS: In this multicenter cohort of neonates who underwent surgery for congenital heart disease, extubation failure occurred in 12% of cases and was associated independently with worse clinical outcome. Use of uncuffed endotracheal tubes and prolonged open sternotomy were identified as independent and potentially modifiable risk factors for the occurrence of this precarious complication.