The susceptibility of the newborn mouse to peroral infection with a group B coxsackievirus (B5) was compared with susceptibility to parenteral infection with this agent. The occurrence, replication, and persistence of virus in various tissues following such infections were also determined. Values for 50% lethal and 50% infectious doses were similar for the two routes of infection. Titer and persistence of virus and pathologic findings were also generally similar. These data indicate that the gut of the newborn mouse does not provide an effective barrier against peroral infection with coxsackievirus B. The newborn mouse perorally infected with group B coxsackievirus appears to provide an excellent model for infection with these agents in the newborn human.