The aims of the present study were to assess the efficacy of a tube weaning program, and to identify factors associated with success and failure. This was a retrospective cohort study including all pediatric patients on enteral nutrition (EN) for ≥6 months for whom at least 1 attempt of weaning was performed in a single tertiary referral center from 2012 to 2017, with a minimum follow-up of 6 months after EN discontinuation. Weaning program was individualized to each child. Weaning success was defined a priori. Factors associated with success were investigated using multivariate analysis. Ninety-four patients were enrolled, in whom a total of 114 attempts of weaning were performed at a median age of 51 ± 40 months. Success was achieved in 80 attempts (success rate of 70%). One hundred three (92%) weaning attempts were performed at home with a follow-up in the outpatient clinic, mostly (74%) by a progressive (>1 month) reduction of tube feeding. Patients who required psychological support during weaning had more failures than patients who did not (odds ratio = 5.7, 95% confidence interval [1.2-27.0], P = 0.03). The presence of impaired oral feeding skills at the time of EN discontinuation was also predictive of failure (odds ratio = 6.2, 95% confidence interval [0.05-0.5], P = 0.005). Our progressive, mostly outpatient-based, patient-tailored program of weaning from EN is effective for tube-dependent children. Children who need psychological support during weaning and those who present impaired oral feeding skills represent a subgroup of at-risk patients for whom alternative weaning strategies may need to be considered.