The supramucosal barrier protects the underlying epithelium from lumenal aggressors. Mucins and trefoil peptides are important components of the protective mucosal barrier in the intestinal mucosa and play a fundamental role in epithelial repair and restitution (1 – 4). Necrotising enterocolitis (NEC) is the most common gastrointestinal (GI) emergency in the human neonate (5). The mechanisms leading to severe necrosis of the bowel and multiorgan failure are poorly understood. The role of mucosal protection in the pathogenesis of NEC has not been investigated. We propose that prematurity is associated with an inefficient mucosal barrier, due in part to abberant trefoil peptide and mucin synthesis and secretion (1, 2, 4). We have examined the expression of MUC1-5AC and TFF 1-3 mRNA and mapped the gene product distribution in the GI tract of fetuses, neonatal controls, and infants with NEC. Consent was obtained from the parents of neonates up to 44 weeks gestation having a laparotomy and bowel resection. The bowel samples from resection specimens, and GI tract extractions from products of conception at termination of pregnancy were collected. Trefoil and mucin mRNA expression and protein localisation was determined by real time PCR, in situ hybridisation and immunohistochemistry. A total of 15 fetal and 44 postnatal (24 with NEC, 16 acute, 8 recovery phase) and 20 control samples were analysed in this study. Fetal mucin and trefoil gene and protein expression in the first trimester showed the same pattern as described in mature bowel (1, 2, 4). Expression of both membrane bound and secreted mucins was unaffected by NEC. Low levels of TFF 1-2 mRNA and protein were detected in the NEC specimens with no evidence for co-ordinated upregulation. A significant downregulation of TFF3 expression was found in 83% of NEC patients. Immunohistochemistry revealed a decrease in TFF3 protein adjacent to areas of mucosal injury in NEC. Our results suggest a lack of TFF expression in response to NEC in the premature bowel, while mucosal barrier mucin is preserved. This may lead to weakened barrier function and impaired mucosal restitution, and contribute to the cascade of bowel necrosis and generalised sepsis characteristic of NEC.