Neonatal sepsis continues to be one of the major causes of morbidity and mortality in the newborn period around the world. India, with one of the world's largest populations, continues to struggle with extremely high infant and neonatal mortality rates. Sepsis accounts for 50% of deaths among community- born (and 20% of mortality among hospital-born) infants. Closely linked with this is a burgeoning problem with antimicrobial resistance, which is increasingly restricting the therapeutic options for medical care providers. To deal with these critical issues, under the auspices of the NICHD Global Network, we have conducted population-based surveillance of sepsis in babies up to 60 days of age and have documented that more than 90% of deaths are due to late onset sepsis. Laboratory and clinical data suggest that administration of Probiotics (friendly bacterial strains that are part of the normal intestinal microflora) has a therapeutic and prophylactic role in specific gastrointestinal conditions, and, possibly, in neonatal conditions including sepsis. Using a well-defined, commercially available supplement of Lactobacillus plantarum (FDA registered in the U.S.), we have performed a hospital- based study at our Indian collaborating centers that has demonstrated safety and colonizing ability of this strain when administered orally to neonates with a corresponding reduction in Gram (-) bacterial load (colony count) at month 1 and 2. To the contrary, Gram (+) bacterial load including Lactobacillus was higher at month 1 and 2 and continued through month 6. Based on in vitro and animal studies, which suggest that this and similar strains block bacterial translocation across the intestinal mucosa, we hypothesize that administration of this strain will facilitate more rapid generation of normal intestinal microflora, and reduced translocation of bacteria from the intestine with a corresponding decrease in the rate of late onset neonatal sepsis. To test this hypothesis, in the current grant, we are proposing to conduct a double blind, randomized, controlled trial of this preparation in 8442 newborn infants in 223 rural villages known to have high rates of neonatal sepsis. A successful outcome would provide a simple, locally available, and inexpensive preventive therapy for dramatically reducing neonatal infections, and in turn, infant mortality in India and other developing countries.