BACKGROUND Probiotics and prebiotics have strain-specific effects on the host. Synbiotics, a mixture of probiotics and prebiotics, are proposed to have more beneficial effects on the host than either agent has alone. OBJECTIVE We performed a randomized controlled trial to investigate the effect of Lactobacillus and Bifidobacterium together with oligosaccharides and lactoferrin on the development of necrotizing enterocolitis (NEC) or sepsis in very low birth weight neonates. METHODS Neonates with a gestational age ≤32 weeks and birth weight ≤1,500 g were enrolled. The study group received a combination of synbiotics and lactoferrin, whereas the control group received 1 mL of distilled water as placebo starting with the first feed until discharge. The outcome measures were the incidence of NEC stage ≥2 or late-onset cultureproven sepsis and NEC stage ≥2 or death. RESULTS Mean birth weight and gestational age of the study (n=104) and the control (n=104) groups were 1,197±235 g vs. 1,151±269 g and 29±1.9 vs. 28±2.2 weeks, respectively (P>0.05). Neither the incidence of NEC stage ≥2 or death, nor the incidence of NEC stage ≥2 or late-onset culture-proven sepsis differed between the study and control groups (5.8% vs. 5.9%, P=1; 26% vs. 21.2%, P=0.51). The only significant difference was the incidence of all stages of NEC (1.9% vs. 10.6%, P=0.019). CONCLUSIONS The combination of synbiotics and lactoferrin did not reduce NEC severity, sepsis, or mortality.