Antibodies play a pivotal role against viral infection, and maintenance of protection is dependent on plasma and memory B-cells. Understanding antigen-specific B-cell responses in cattle is essential to inform future vaccine design. We have previously defined T-cell-dependent and -independent B-cell responses in cattle, as a prelude to investigating foot-and-mouth-disease-virus (FMDV)-specific B-cell responses. In this study, we have used an FMDV O-serotype vaccination (O1-Manisa or O SKR) and live-virus challenge (FMDV O SKR) to investigate the homologous and heterologous B-cell response in cattle following both vaccination and live-virus challenge. The FMDV O-serotype vaccines were able to induce a cross-reactive plasma-cell response, specific for both O1-Manisa and O SKR, post-vaccination. Post-FMDV O SKR live-virus challenge, the heterologous O1-Manisa vaccination provided cross-protection against O SKR challenge and cross-reactive O SKR-specific plasma cells were induced. However, vaccination and live-virus challenge were not able to induce a detectable FMDV O-serotype-specific memory B-cell response in any of the cattle. The aim of new FMDV vaccines should be to induce memory responses and increased duration of immunity in cattle.