Interferons (IFNs) contribute to cell-intrinsic antiviral immunity by inducing hundreds of IFN-stimulated genes (ISGs). In a screen to identify antiviral ISGs, we unexpectedly found that lymphocyte antigen 6 complex, locus E (LY6E) enhanced viral infection. Here, we characterize the mechanism of LY6E-mediated viral enhancement in vitro and demonstrate a role for Ly6e in influenza A virus pathogenesis in vivo. Using common genetic approaches, we show that ectopic expression of LY6E enhances cellular infection by a subset of enveloped RNA viruses from diverse families. Conversely, ablation of endogenous LY6E by CRISPR/Cas9 reduces viral infectivity. We further demonstrate that LY6E is not a negative regulator of IFN since it has no effect on IFN antiviral activity, IFN signaling, or global cellular transcription. Mechanistically, we narrow the enhancing effect of LY6E to a post-binding viral entry step, prior to the onset of replication. Using alanine scanning mutagenesis, we also identify a single amino acid that is required for viral enhancement. These in vitro studies are complemented by generation of a novel Ly6e knockout mouse. Conditional ablation of Ly6e in CD11c+ cells increased susceptibility to influenza A virus, indicating that viral enhancement by Ly6e in a subset of immune cells may contribute to cell-mediated antiviral immunity. Our study suggests that LY6E belongs to a novel class of ISGs that may directly enhance viral infectivity of individual cells to bolster the host antiviral immune response.