Lactoferrin, a normal component of human colostrum, milk, tears and saliva can enhance host defence and may be effective in the prevention of sepsis and necrotizing enterocolitis (NEC) in preterm neonates. To assess the safety and effectiveness of oral lactoferrin in the prevention of sepsis and NEC in preterm neonates. We used the search strategy of the Cochrane Neonatal Review Group (CNRG) including searches of CENTRAL (The Cochrane Library), MEDLINE and PREMEDLINE, EMBASE and CINAHL. We also searched trials registries and the conference proceedings of Pediatric Academic Society. Searches updated in July 2011. Randomized or quasi-randomized controlled trials evaluating oral lactoferrin at any dose or duration for the prophylaxis of sepsis or NEC in preterm neonates. Data collection and analysis were performed according to the standard methods of the CNRG. One trial (Manzoni 2008) that randomized 472 very low birth weight infants was eligible. A statistically significant reduction in late-onset sepsis was observed in the groups that received either lactoferrin alone (RR 0.34, 95% CI 0.17 to 0.70) or in combination with Lactobacillus rhamnosus GG (RR 0.27, 95% CI 0.12 to 0.60).In subgroup analyses, infants weighing less than 1000 g and those fed exclusively on maternal milk had a significant reduction in late-onset sepsis after oral lactoferrin supplementation alone. In the group supplemented with oral lactoferrin and Lactobacillus rhamnosus, infants weighing less than 1000 g had a significant reduction in late-onset sepsis, a result not seen in infants fed maternal milk exclusively.Prophylaxis with oral lactoferrin alone did not reduce the incidence of NEC (RR 0.33, 95% CI 0.09 to 1.17), but a significant reduction in NEC with a combination of lactoferrin and Lactobacillus rhamnosus GG was noted (RR 0.05, 95% CI 0.00 to 0.90).No adverse effects due to lactoferrin were observed in this study. Long-term neurological outcomes were not assessed in this trial. Oral lactoferrin prophylaxis reduces the incidence of late-onset sepsis in infants weighing less than 1500 g and most effective in infants weighing less than 1000 g. There is no evidence of efficacy of oral lactoferrin (given alone) in the prevention of NEC in preterm neonates.Well designed, randomized trials should address dosing, duration, type of lactoferrin (bovine or human) prophylaxis in prevention of sepsis and NEC. The effect of exclusive maternal milk feeding should be clarified.