Necrotizing enterocolitis (NEC) is a common and devastating gastrointestinal disease that occurs predominantly in premature infants. Despite various advances in management, the mortality of this disease remains high. During the last decade, studies from our laboratory have shown that heparin-binding epidermal growth factor-like growth factor (HB-EGF), a member of the epidermal growth factor (EGF) family, can protect intestinal epithelial cells (IEC) from various forms of injury in vitro. Furthermore, we have used both an intestinal I/R injury model in adult rats, and a neonatal rat pup model of NEC, to show that HB-EGF can protect the intestines from injury. On administration of HB-EGF in the neonatal rat model, the incidence of NEC is reduced from 65% to 27.3% (P < 0.05), and the histological injury score is decreased from 2 to 1.1 (P < 0.05). In addition, the survival rate is increased from 25% to 63.6% and the survival time extended from 59 hours to 73 hours (P < 0.05). In addition, using human specimens from newborns undergoing bowel resection for NEC, we found that the expression of endogenous HB-EGF mRNA in normal areas of the intestine at the resection margins was higher than that of the intestine afflicted with acute NEC. Endogenous HB-EGF may be involved in epithelial cell repair, proliferation, and regeneration during recovery from injury. Exogenous administration of HB-EGF potentiates recovery from intestinal injury in vitro and in vivo. Taken together, these results support a potential therapeutic role for HB-EGF in the treatment of NEC in the future.