Vaccinia virus (VACV) exhibits a strong tropism for ovarian tissue and can cause ovary pathology and sterility. Why VACV preferentially accumulates in this organ is not known. Here we show that multiple immune cell populations infiltrated the ovaries following VACV infection, including virus-specific CD8 T cells making both IFN-γ and TNF. This was also accompanied by the induction of interleukin (IL)-10 and TGF-β, suggesting that VACV may exploit the ovarian environment for immune evasion via induction of these suppressive cytokines. To test this we used several strategies, including neutralizing these cytokines, and exogenous targeting of the T-cell response, to determine if this inhibited virus replication in the ovaries. We found that the VACV-specific CD8 T-cell immunity and the clearance of virus were not enhanced in the ovaries of infected mice in which IL-10 receptor (IL-10R) was blocked with antagonist antibody. VACV replication was also only moderately affected in the ovaries of infected IL-10 knockout mice. Similarly, blockade of TGF-β with antagonist antibody demonstrated no effect on CD8 T-cell immunity or VACV replication. Lastly, an agonist antibody targeting the tumor necrosis factor receptor superfamily member OX40 (TNFRSF4) enhanced the number of VACV-specific CD8 T cells producing IFN-γ in lymphoid tissue, but had no effect on CD8 T-cell infiltration of the ovaries or on the viral load. Collectively, the results indicate that preferential replication of VACV in the ovaries may not be dependent on immune suppressive mechanisms in this tissue