Toll-like receptors (TLR) are members of a highly conserved group of receptors wh1ch recognize conserved molecular aspects of microbes. The purpose of these experiments were to ascertain the effects of the administration of the TLR 9 agonist, CpG, on the colonization of neonatal swine with Salmonella. Piglets were treated within 24 hr after birth (Day 0) with CpG via oral gavage. On day 5 post-treatment, piglets were challenged with Salmonella orally. Daily rectal swabs were taken until day 10 post-treatment. On day 10, piglets were euthanized and gut contents and tissues were cultured for the presence of Salmonella. Piglets in the CpG group had a one log reduction of Salmonella in cecal and colon contents, and no Salmonella was detected in rectal contents in this group compared with Salmonella infected control pigs. Rectal swabs showed a reduction in fecal shedding of Salmonella on days 7-10 in CpG treated pigs. No Salmonella was detected in any pigs treated with CpG in the spleen or rectum. Reductions in the number of pigs positive for Salmonella were found in the lymph nodes, colon and cecum. The data show that CpG may be an effective tool in reducing Salmonella colonization and shedding in neonatal pigs and supports previous data in weaned pigs where CpG had similar effects on Salmonella colonization.