Batf3-dependent intestinal CD103(+) dendritic cells (DCs) play a key role in controlling the acute phase of the infection and are also instrumental for the definitive clearance of the parasite. Intestinal CD103(+) DCs outperform CD103 DCs in controlling Cryptosporidium parvum infection.Understanding the protective immune response to Cryptosporidium parvum infection is of critical importance to reduce the widespread impact caused by this disease in young individuals. Here, we analyzed the various subsets of CD103(+) and CD103 intestinal dendritic cells (DCs) of wild-type and Batf3(/) neonatal mice at homoeostasis and investigated their role during infection. Neonatal Batf3(/) mice had a low CD103(+)/CD103 DC ratio, resulting in higher susceptibility to the acute phase of the infection and they could not cure the infection. Early during infection, CD103 DCs of Batf3(/) neonates had a lower ability to produce interleukin-12 than their wild-type littermates and lower levels of interferon-gamma mRNA were detected in the infected mucosa. Amplification of CD103(+) DCs in Batf3(/) neonates prior to infectious challenge reduced their susceptibility to infection. CD103(+) DCs thus outperform CD103 DCs in controlling C. parvum infections and represent a primary target of host-directed immunotherapies dedicated to neonates.