© 2015 The American Society for Parenteral and Enteral Nutrition.Introduction: Prevention of necrotizing enterocolitis (NEC) while optimizing enteral nutrition (EN) is a priority in preterm neonates. Lactobacillus reuteri DSM 17938 (L reuteri) is known to improve gut motility. Previous systematic reviews have not adequately assessed the effects of L reuteri in improving feed tolerance in preterm neonates. Objective: To assess the effects of L reuteri in preterm neonates. Design: A systematic review of randomized controlled trials (RCTs) and non-RCTs of L reuteri was conducted. We searched the Cochrane Central Register of Controlled Trials, PubMed, EMBASE, and CINAHL databases and proceedings of Pediatric Academic Society meetings in December 2014. Results: Six RCTs (n = 1778) and 2 non-RCTs (n = 665) were included. Meta-analysis of RCTs estimated that the time to full feeds (mean difference [MD], -1.34 days; 95% confidence interval [CI], '1.81 to '0.86; 2 RCTs), duration of hospitalization (-10.77 days; 95% CI, '13.67 to '7.86; 3 RCTs), and late-onset sepsis (LOS) (relative risk [RR], 0.66; 95% CI, 0.52 to 0.83; 4 RCTs) were reduced in the L reuteri group. Mortality (RR, 0.79; 95% CI, 0.57-1.09; 3 RCTs) and = stage II NEC (RR, 0.69; 95% CI, 0.47-1.01; 3 RCTs) were reduced but statistically not significant. There were no adverse effects of supplementation. Both non-RCT studies showed significant improvement in the incidence of NEC with L reuteri supplementation. Conclusions: Evidence from a limited number of studies suggests that L reuteri supplementation has the potential to reduce the risk of NEC and LOS while facilitating EN in preterm infants. Larger definitive RCTs are needed to confirm these findings.