It has been suggested that probiotics may decrease infant mortality and nosocomial infections because of their ability to suppress colonization and translocation of bacterial pathogens in the gastrointestinal tract. We designed a large double-blinded placebo-controlled trial using Lactobacillus reuteri to test this hypothesis in preterm infants.Eligible infants were randomly assigned during the first 48 hours of life to either daily probiotic administration or placebo. Infants in the intervention group were administered enterally 5 drops of a probiotic preparation containing 10(8) colony-forming units of L reuteri DSM 17938 until death or discharge from the NICU.A total of 750 infants ≤ 2000 g were enrolled. The frequency of the primary outcome, death, or nosocomial infection, was similar in the probiotic and placebo groups (relative risk 0.87; 95% confidence interval: 0.63-1.19; P = .376). There was a trend toward a lower rate of nosocomial pneumonia in the probiotic group (2.4% vs 5.0%; P = .06) and a nonsignificant 40% decrease in necrotizing enterocolitis (2.4% vs 4.0%; P = .23). Episodes of feeding intolerance and duration of hospitalization were lower in infants ≤ 1500 g (9.6% vs 16.8% [P = .04]; 32.5 days vs 37 days [P = .03]).Although L reuteri did not appear to decrease the rate of the composite outcome, the trends suggest a protective role consistent with what has been observed in the literature. Feeding intolerance and duration of hospitalization were decreased in premature infants ≤ 1500 g.