Objective: To identify the predictors of prolonged mechanical ventilation (PMV) after cardiopulmonary bypass (CPB) in infants with congenital heart disease (CHD) less than 3 months. Methods: From June 2017 to May 2020, a total of 165 infants less than 3 months old with CHD admitted to the Children’s Hospital of Nanjing Medical University for CPB were enrolled. The following data were collected including gender, age, weight, Risk Adjustment in Congenital Heart Surgery-1 (RACHS-1) score, preoperative levels of thyroid hormones, CPB time, aortic cross-clamping (ACC) time, mechanical ventilation time, ICU mortality and infection. PMV prediction was assessed by multivariate binary logistic regression analysis. Results: Compared with non-PMV group, PMV group was younger (44.74±25.27 days vs. 35.44±26.91 days, P= 0.001), and most were newborns (41/93 vs. 10/57, P=0.000), with a higher proportion of RACHS-1 (29/93 vs.6/57, P=0.000) and more cases of infection (47/93 vs. 17/57,P= 0.004).PMV group had significantly lower weight than non-PMV group (3.79±0.83Kg vs. 4.28±1.01Kg, P=0.001). In PMV group, CPB (133.74±89.65 vs. 72.30±44.82, P =0.000) and ACC time (52.02± 24.80 vs. 36.98±16.63, P =0.000) were both longer. FT4 and TT4 were higher while FT3, TT3 and TSH were lower in PMV group, but only FT3 (4.99±1.67 vs. 5.29± 1.23, P =0.017) and TT3 (1.91±0.59 vs. 1.96±0.49, P =0.050) showed significant differences between PMV group and non-PMV group. Conclusion: Multiple logistic regression analysis showed that weight, infection, FT3 and CPB time were independent predictors of PMV after CPB in infants with CHD.