Vaccinia virus (VACV) strain MVA is a highly attenuated vector for vaccines that is being explored in clinical trials. We compared the CD8(+) T-cell immunogenicity of MVA with that of a virulent laboratory strain of VACV (strain WR) in BALB/c mice by examining epitope-specific responses as well as estimating the total number of activated CD8(+) T cells, irrespective of specificity. We found that MVA elicited total CD8(+) T-cell responses that were reduced by at least 20-fold compared with strain WR in BALB/c mice. In C57Bl/6 mice, we also found a substantial difference in immunogenicity between these VACV strains, but it was more modest at around fivefold. Of note, the size of responses to the virulent WR virus was similar in both strains of mice suggesting that BALB/c mice can mount robust CD8(+) T-cell responses to VACV. Although the data for total responses clearly showed that MVA overall is poorly immunogenic in BALB/c mice, we found one epitope for which strong responses were made irrespective of virus strain. Therefore, in the context of a vaccine, some recombinant epitopes may have similar immunogenicity when expressed from MVA and other strains of VACV, but we would expect these to be exceptions. These data show clearly the substantial difference in immunogenicity between MVA and virulent VACV strains and suggest that the impact of host genetics on responses to attenuated vaccine vectors like MVA requires more consideration.Immunology and Cell Biology advance online publication, 25 February 2014; doi:10.1038/icb.2014.10.