To identify maternal and neonatal factors that impact response to methadone therapy for neonatal abstinence syndrome. This is a retrospective review of 128 infants that received pharmacotherapy for opiate withdrawal to identify factors associated with favorable response to methadone therapy. Maternal and neonatal data were analyzed with univariate statistics and multivariate logistic regression. Maternal methadone maintenance dose during pregnancy correlated with length of stay (P=0.009). There was an inverse correlation between the amount of mother's breast milk ingested and length of stay (β=-0.03, P=0.02). Methadone was initiated later, tapered more rapidly and was more successful as monotherapy in preterm infants. Five percent of infants were admitted to hospital again for rebound withdrawal following reduction of breast milk intake. Severity of neonatal abstinence syndrome may be mitigated by titrating methadone to the lowest effective dose during pregnancy and by encouraging breast milk feeds, which should be weaned gradually.