Vaccinia virus (VACV) is a notorious virus for a number of scientific reasons; however, most of its notoriety comes from the fact that it was used as a vaccine against smallpox, being ultimately responsible for the eradication of that disease. Nonetheless, many different vaccinia virus strains have been obtained over the years; some are suitable to be used as vaccines, whereas others are virulent and unsuitable for this purpose. Interestingly, different vaccinia virus strains elicit different immune responses in vivo, and this is a direct result of the genomic differences among strains. In order to evaluate the net result of virus-encoded immune evasion strategies of vaccinia viruses, we compared antiviral immune responses in mice intranasally infected by the highly attenuated and nonreplicative MVA strain, the attenuated and replicative Lister strain, or the virulent WR strain. Overall, cell responses elicited upon WR infections are downmodulated compared to those elicited by MVA and Lister infections, especially in determined cell compartments such as macrophages/monocytes and CD4+ T cells. CD4+ T cells are not only diminished in WR-infected mice but also less activated, as evaluated by the expression of costimulatory molecules such as CD25, CD212, and CD28 and by the production of cytokines, including tumor necrosis factor alpha (TNF-α), gamma interferon (IFN-γ), interleukin-4 (IL-4), and IL-10. On the other hand, MVA infections are able to induce strong T-cell responses in mice, whereas Lister infections consistently induced responses that were intermediary between those induced by WR and MVA. Together, our results support a model in which the virulence of a VACV strain is proportional to its potential to downmodulate the host's immune responses.IMPORTANCE Vaccinia virus was used as vaccine against smallpox and was instrumental in the successful eradication of that disease. Although smallpox vaccination is no longer in place in the overall population, the use of vaccinia virus in the development of viral vector-based vaccines has become popular. Nonetheless, different vaccinia virus strains are known and induce different immune responses. To look into this, we compared immune responses triggered by mouse infections with the nonreplicative MVA strain, the attenuated Lister strain, or the virulent WR strain. We observed that the WR strain was capable of downmodulating mouse cell responses, whereas the highly attenuated MVA strain induced high levels of cell-mediated immunity. Infections by the intermediately attenuated Lister strain induced cell responses that were intermediary between those induced by WR and MVA. We propose that the virulence of a vaccinia virus strain is directly proportional to its ability to downmodulate specific compartments of antiviral cell responses.