Background: Probiotics are live microorganisms which when administered in adequate amounts confer a health benefit on the host. Probiotics have been used for prevention and treatment of various medical conditions in children and adults. Studies on probiotics in premature infants have focused on normalizing intestinal flora, improvement in feeding intolerance, prevention of necrotizing enterocolitis which is the leading causes of death in the neonatal intensive care unit.  Objective of the Study: was to provide an overview of the controversies regarding probiotic use in preterm infants and to shed light on the practical considerations for implementation of probiotic supplementation. Methods: A Systematic search in the scientific database (Medline, Scopus, EMBASE , and Google Scholer) from 1990 to 2016 was conducted for all relevant retrospective studies including; retrospective , prospective and randomized controlled trials and cohort studies were analyzed and included based on the preset inclusion and exclusion criteria. Results: The search results yielded 16 studies, 12 of which were RCTs with 2340 premature neonates and 4 meta-analyses with 10227 neonates which showed a significantly decreased incidence of Necrotizing Enterocolitis (NEC) (risk ratio, RR = 0.35, 95% confidence interval, 95% CI, 0.23-0.54; p = 0.0006) and mortality (RR = 0.46, 95% CI, 0.32-0.67; p < 0.0001). Sepsis did not differ significantly between the two groups (RR = 0.93, 95% CI, 0.76-1.15; p = 0.05). Conclusion: there is a strong body of evidence supporting that Probiotic supplementation reduces the risk of NEC and mortality in preterm infants yet there is no sufficient evidence to support the optimal strain, dose and timing need further investigation.