Foot-and-mouth disease virus (FMDV) is a picornavirus that causes an acute vesicular disease of cloven-hoofed animals. This virus continues to be threat to livestock worldwide with outbreaks causing severe economic losses. However, very little is known about FMDV pathogenesis, partially due to the inconveniences of working with cattle and swine, the main natural hosts of the virus. Here we demonstrate that C57BL/6 and BALB/C adult mice are highly susceptible to FMDV infection when the virus is administered subcutaneously or intraperitoneally. The first clinical signs are ruffled fur, apathy, humped posture, and wasting, which are followed by neurological signs such as hind-limb paralysis. Within 2-3 days of disease onset, the animals die. Virus is found in all major organs, indicating a systemic infection. Mice developed microvesicles near the basal layer of the epithelium, event that precedes the vesiculation characteristics of FMD. In addition, a lymphoid depletion in spleen and thymus and severe lymphopenia is observed in the infected mice. When these mice were immunized with conventional inactivated FMDV vaccine, they were protected (100% of vaccinated animals) against challenge with a lethal dose of FMDV. The data indicate that this mouse model may facilitate the study of FMDV pathogenesis, and the development of new effective vaccines for FMD.