Zika virus (ZIKV) is a re-emerging flavivirus that normally causes mild non-specific symptoms in adults but can cause severe developmental disease in neonates when exposed in utero. Primarily transmitted by mosquitoes, ZIKV can also be transmitted sexually. Prevention of ZIKV sexual transmission is important in the global defence against this pathogen. Typically, type I IFNs (IFN) are produced in response to viral infection and are crucial to controlling ZIKV infection. However, the newly discovered type-I IFN; IFNε, is constitutively expressed predominately in the female reproductive tract (FRT) in both mice and humans. IFNε is controlled by the female sex hormones with expression highest during estrous and least during diestrous. Therefore, it is possible that IFNε is preventive of ZIKV infections in the FRT. To investigate IFNε’s role in preventing ZIKV infections we first used an in vitro cell culture model that revealed IFNε can significantly block ZIKV replication (qRT-PCR, plaque assay) similar to IFNα/β. Furthermore, the canonical JAK/STAT pathway was activated with concomitant ISG expression following IFNε stimulation. However, ZIKV shuts down this antiviral response through NS5 mediated degradation of STAT2 in similar manner to that previously demonstrated for IFNα. To explore the role of IFNε in vivo we intravaginally inoculated IFNε-/- mice with ZIKV (PRVABC59, 5 x 105 PFU/mL). IFNε-/- mice had increased viral burden in the FRT as assessed by qRT-PCR and recovery of infectious virus by plaque assay in vaginal washes when compared to WT mice. Interestingly, viral burden was similar between vaginal washes from IFNε-/- and IFNAR1-/-mice suggesting that IFNε-/- plays an important role early in infection of the FRT. These findings highlight the role of IFNε-/- in prevention of ZIKV infections of the FRT and may lead to changes in health advice or immune based therapies for ZIKV infections in women.