It is not possible to diagnose FMD based solely on the histologic appearance of the disease, as all vesicular diseases have similar histopathologic characteristics. There is intra- and intercellular edema in large rafts of cells within the stratum spongiosum. Once the vesicles have ruptured, the histology of vesicular diseases is very similar to many erosive and ulcerative diseases.

Foot-and-mouth disease virus does not produce any observable viral inclusions.