We observed minimal up-regulation of co-stimulatory and MHC molecules, inflammatory cytokine secretion, as well as antagonism of type I IFN translation during ZIKV infection, despite notable transcriptional up-regulation of IFNB1. Despite this, ZIKV infection induced an antiviral state as noted by strong up-regulation of the RLRs (RIG-I, MDA5, and LGP2), STAT proteins (STAT1 and 2), and antiviral effectors (IFIT1, IFIT3, and viperin). Here, RIGI is linked to Zika virus infectious disease.