Field strains of Foot-and-mouth disease virus (FMDV) use a number of alpha(v)-integrins as receptors to initiate infection on cultured cells, and integrins are believed to be the receptors used to target epithelial cells in animals. In this study, immunofluorescence confocal microscopy and real-time RT-PCR were used to investigate expression of two of the integrin receptors of FMDV, alpha(v)beta6 and alpha(v)beta3, within various epithelia targeted by this virus in cattle. These studies show that alpha(v)beta6 is expressed constitutively on the surfaces of epithelial cells at sites where infectious lesions occur during a natural infection, but not at sites where lesions are not normally formed. Expression of alpha(v)beta6 protein at these sites showed a good correlation with the relative abundance of beta6 mRNA. In contrast, alpha(v)beta3 protein was only detected at low levels on the vasculature and not on the epithelial cells of any of the tissues investigated. Together, these data suggest that in cattle, alpha(v)beta6, rather than alpha(v)beta3, serves as the major receptor that determines the tropism of FMDV for the epithelia normally targeted by this virus.