Background and Aim: Breast milk has been shown to be associated with greater success with regard to weaning children with intestinal failure off parenteral nutrition (PN). There are only a few studies investigating the role of breast milk in decreasing PN-associated liver disease (PNALD). The aim of our study was to determine whether breast milk is better than formula milk in preventing PNALD in infants receiving PN for >4 weeks. Methods: We conducted a retrospective analysis of newborns requiring prolonged parenteral nutrition. We divided the sample into 3 different groups (exclusive breast-feeding, exclusive formula-feeding, and mixed feeding. We compared baseline characteristics, feeding profiles and liver function tests, and liver enzymes among the 3 groups. Results: Among infants receiving PN for >4 weeks, we found that infants who were fed only breast milk were significantly less likely to develop PNALD (34.6%) compared with those who were fed only formula milk (72.7%; P¼0.008). The mean maximum conjugated bilirubin (P¼0.03) and the mean maximum aspartate aminotransferase were significantly lower in the breast-fed group (P¼0.04) compared with the formula-fed group. Among the mixed-feeding group, infants who received a higher percentage of breast milk showed a significant negative correlation with the mean maximum conjugated bilirubin. (Pearson correlation 0.517, P¼0.027). The mean number of days receiving PN and the average daily lipid intake in the 2 groups was not significantly different. Conclusions: As a modality for early enteral nutrition, breast milk is protective against the development of PNALD in infants receiving PN for >4 weeks.