Background. Neonates are particularly vulnerable to infections, in part because of the incomplete development of their immune system. Recent advances in immunostimulatory treatments based on conserved microbial components led us to assess the potential of oligodeoxynucleotides ( ODNs) for decreasing the sensitivity of neonates to Cryptosporidium parvum infection. Methods. Neonate mice were treated orally or intraperitoneally ( ip) with CpG ODNs or non-CpG ODNs 24 h before C. parvum infection, and parasite load and cytokine up-regulation were evaluated. Results. CpG ODN 1668 and non-CpG ODN 1668 administered orally, as well as CpG ODN 1668 administered ip, induced an 80%-95% decrease in intestinal parasite load 6 days after infection. Intraperitoneal and oral pretreatment with CpG ODN 1668 led to a strong initial up-regulation of cytokines and CD69 messenger RNA in the intestine and a decrease in parasite load by a Toll-like receptor 9 ( TLR9)-dependent mechanism. By contrast, oral administration of non-CpG ODN 1668 decreased parasite load by a TLR9-independent mechanism. Conclusion. The control of neonatal C. parvum infection by ip or oral administration of ODNs is feasible by 2 different mechanisms: ( 1) the well-known interaction involving CpG/TLR9, leading to the production of cytokines and lymphocyte activation, and ( 2) a new unknown mechanism that is independent of TLR9 and effective orally.