Importantly, our work suggests that stronger ISG15‐USP18 binding (reliant on the ISG15 C‐terminal tail) is required for USP18‐dependent regulation of the type I IFN response as the level of binding to USP18 reflected the level of IFN‐α signalling regulation and the permissiveness of cells to viral infection. This evidence concerns the gene IFNA2 and viral infectious disease.