West Nile virus (WNV) and Zika virus (ZIKV) infections inhibit pY-STAT and gene expression in response to multiple cytokines. pY-STAT responses were inhibited in WNV- and ZIKV-infected A549 cells at 30 min post-treatment with (A,B) inferno (IFN)β, (C,D) 10 ng/mL IFNγ (arrow heads), (E) IFNλ3, (F,G) interleukin (IL)6, and (H,I) IL4. WNV-infected A549 cells did not respond to 17 h treatment with (J) IFNβ (IFITM1 and IFIT1 induction) or (K) IL6 (γFibrinogen and IGFBP1 induction). (L) WNV-infected PH5CH8 IFNAR1−/− cells did not respond to 24 h IFNλ3 treatment via expression of the interferon stimulated genes MX1, IFIT1, OAS1, and ISG15. All infections were MOI = 5 for 24 h prior to cytokine treatment unless otherwise stated. All data represent three independent experiments or are a combination of three experiments (mean ± standard error of the mean (SEM)). See also Figure S1. **** = p < 0.0001, *** = p < 0.001, ns = p > 0.05. Two-way ANOVA with Tukey’s posttests.