Background: Growing antibiotic resistance and debates over their efficacy for urinary tract infection (UTI) recurrence warrants studying nonantibiotic prophylaxis for preventing UTI recurrences. Methods: We randomly assigned 181 children, aged 4 months to 5 years, with a normal urinary tract after recovery from their first febrile UTI in a 1:1 ratio to receive a probiotic mixture of Lactobacillus acidophilus, Lactobacillus rhamnosus, Bifidobacterium bifidum, and Bifidobacterium lactis (n = 91) or placebo (n = 90) for a total of 18 months of therapy. The primary objective was to show the superiority of probiotic prophylaxis to placebo. The primary end point was composite cure (UTI-free survival) at 18 months, and the secondary end point was the median time to first UTI recurrence. Results: The probiotics were superior to placebo with respect to the primary efficacy end point. At 18 months, composite cure was observed in 96.7% (3 of 91) of the patients in the probiotic group and 83.3% (15 of 90) of those in the placebo group (P = .02). The median time to the first incidence of UTI recurrence was 3.5 months (range, 1–4 months) and 6.5 months (range, 2–14 months) in the probiotic and placebo groups, respectively (P = .04). The main microorganism that caused recurrent UTI was Escherichia coli, followed by Klebsiella pneumoniae, and these results were not significantly different between the 2 groups. We found no specific adverse events among the participants who received the probiotic mixture during the course of therapy. Conclusions: The probiotics were more effective than placebo at reducing the risk of recurrent UTI in children with a normal urinary tract after their first episode of febrile UTI.