Oligodeoxynucleotides (ODN) containing unmethylated CpG motifs are potent stimulators of the innate immune system, and are capable of aborting several infections in a non-specific manner. We here report studies of the capacity of such ODN to protect mice against infection with foot and mouth disease virus (FMDV). Susceptibility of Balb/c mice to infection with isolates from the different serotypes of FMDV was investigated, and, at the same time, the capacity of CpG ODN to modulate the infection was evaluated. Treatment with CpG significantly reduced viremia, disease and death in five of six serotypes, when compared to no treatment or treatment with a control ODN. The effect was observed when ODN was administered simultaneously with, or up to 12h after, infection with FMDV, and lasted for 14 days post treatment. The potential application of CpG ODN for control of FMDV during an outbreak is discussed.