AbstractProtective adaptive immunity to Zika virus (ZIKV) has been mainly attributed to cytotoxic CD8⁺ T cells and neutralizing antibodies, while the participation of CD4⁺ T cells in resistance has remained largely uncharacterized. Here, we show a neutralizing antibody response, dependent on CD4⁺ T cells and IFNγ signaling, which we detected during the first week of infection and is associated with reduced viral load in the brain, prevention of rapid disease onset and survival. We demonstrate participation of these components in the resistance to ZIKV during primary infection and in murine adoptive transfer models of heterologous ZIKV infection in a background of IFNR deficiency. The protective effect of adoptively transferred CD4⁺ T cells requires IFNγ signaling, CD8⁺ T cells and B lymphocytes in recipient mice. Together, this indicates the importance of CD4⁺ T cell responses in future vaccine design for ZIKV.