Background/Objectives: Prebiotics are increasingly recognized as an effective measure to promote health and prevent adverse health outcomes in preterm infants. We aimed to systematically review the randomized controlled trials (RCTs) in this area.

Subjects/Methods: Relevant studies from January 2000 to June 2018 were searched and selected from PubMed, Medline, Scopus, and the Cochrane Library. RCTs were included if they involved preterm infant participants, included a prebiotic intervention group, measured incidence of sepsis, feeding intolerance, mortality, time to full enteral feeding, necrotizing enterocolitis (NEC), length of hospital stay, and stool frequency as outcomes.

Results: Eighteen RCTs (n = 1322) were included in the final meta-analysis. Participants who took prebiotics showed significant decreases in the incidence of sepsis (with a risk ratio (RR) of 0.64, 95% CI: 0.51, 0.78), mortality (RR = 0.58. 95% CI: 0.36, 0.94), length of hospital stay (mean difference (MD): −5.18, 95% CI: −8.94, −1.11), and time to full enteral feeding (MD: −0.99, 95% CI: −1.15, 0.83). The pooled effects showed no significant differences between intervention and control groups in relation to the morbidity rate of NEC (RR = 0.79, 95% CI: 0.44, 1.44) or feeding intolerance (RR = 0.87, 95% CI: 0.52, 1.45).

Conclusions: The results showed that the use of prebiotics with preterm infants is safe and can decrease the incidence of sepsis, mortality, length of hospital stay, and time to full enteral feeding but not NEC.