Recent European guidelines facilitate the use of emergency vaccines during outbreaks of foot-and-mouth disease. Antiviral drugs could be used as a complementary measure. This study aimed at developing a small animal model to assess the in vivo activity of early antiviral lead molecules with anti-foot-and-mouth disease virus (FMDV) activity in vitro. In a first attempt, several FMDV strains were titrated in Balb/c mice. Inoculations with O₁ Manisa or C₁ Noville did not induce clinical disease, whereas Asia1 Shamir induced death too rapidly [i.e. within 4 days post-inoculation (dpi)]. Therefore, we switched to severe combined immunodeficient mice which are frequently used as a model for viral infections and experimental therapeutics. Strain O₁ Manisa did not induce clinical disease, but titrations with A₂₂ Iraq, C₁ Noville or Asia1 Shamir resulted in virus-induced morbidity (including respiratory problems and weight loss) with subsequent mortality. Inoculations with strain A₂₂ Iraq resulted in a reproducible mean time of death of 6 dpi (this was shorter for the other strains). In this newly developed rodent model, strain A₂₂ Iraq seems the most suited to assess the in vivo anti-FMDV activity of selective inhibitors of FMDV.