Abstract Introduction Flavivirus infections are cause of great concern worldwide due to recurrent epidemics and high mortality rates, being a major public health problem. The relevance to study Zika virus infection was highlighted after the discovery that ZIKV infection during pregnancy could cause microcephaly, besides others abnormalities. Knowing that ZIKV, like other flaviviruses, can modulate host innate and adaptive immune response, we aim to understand the role of CD8+ regulatory T cells in the control of viral replication in an experimental infection. Methods C57BL/6 Foxp3GFP and C57BL/6 CD8−/− mice were infected with 106 PFU of ZIKV (Brazilian strain), followed by viral quantification, gene expression, and flow cytometry analysis. Results Infection of CD8 knockout mice presented viral load with an oscillatory profile compared to WT mice, and analysis of CD8 T cells populations in WT mice showed that CD8Foxp3 cells are induced on the first day post infection and it pool of cells are maintained during infection, as could be noted on day 30 post infection. These cells are related to increase of viral replication as shown in cell transfer experiment. However, naïve CD8Foxp3 cells are responsible to increase virus replication, while CD8Foxp3 cells from infected mice seems to be not capable to respond to antigen. Conclusion This finding leads us to believe that there is an attempt by the pathogen to modulate the adaptive immune response, in order to facilitate its replication and permanence in the host. In short, our work seeks to elucidate the immunobiology of the ZIKV infection and to correlate this with the susceptibility to the Congenital Syndrome caused by Zika virus.